CZ2003402A3

CZ2003402A3 - Piperidine derivatives and agent containing these derivatives as active ingredient

Info

Publication number: CZ2003402A3
Application number: CZ2003402A
Authority: CZ
Inventors: Hisao Nakai; Katsuya Kishikawa
Original assignee: Ono Pharmaceutical Co., Ltd.
Priority date: 2000-08-11
Filing date: 2001-08-09
Publication date: 2003-12-17
Also published as: CA2418313C; MXPA03001276A; CN1203058C; EP1308440A1; US20060189656A1; CN1468219A; TWI232858B; PL361360A1; JP3433752B2; AU7773801A; EP1308440B1; CA2418313A1; NO324869B1; US7109342B2; DE60138628D1; HUP0303673A3; IL154231A0; AU2001277738B2; IL154231A; WO2002014280A1

Abstract

Piperidine derivatives represented by formula (I) or nontoxic salts thereof (wherein symbols are defined in the description): <CHEM> Since the compound represented by formula (I) has a PDE4 inhibitory activity, it is useful for preventing and/or treating inflammatory diseases, diabetic diseases, allergic diseases, autoimmune diseases, osteoporosis, bone fracture, obesity, depression, Parkinson's disease, dementia, ischemia-reperfusion injury, leukemia and the like.

Description

Technical field

The invention relates to piperidine derivatives. More particularly, the invention relates to (1) piperidine derivatives of formula (I)

wherein all the general symbols are as defined below, their non-toxic salts;

(2) a process for the preparation of these derivatives; and (3) an agent that contains such a derivative as an active ingredient.

Background Art

Cyclic adenosine 3 ', 5'-monophosphate (cAMP) and cyclic guanosine 3', 5'-monophosphate (cGMP) as intracellular signal transduction molecules (secondary messengers) are degraded by a group of hydrolases commonly referred to as phosphodiesterases (PDEs) to inactive 5-AMP and 5'-GMP.

PDE isozymes that inactivate them in vivo are not evenly distributed, but are distributed in specific organs, with differences in, for example, cell and tissue distribution.

To date, the existence of 11 families, PDE1 to PDE11, has been confirmed (see Current Opinion in Cell Biology, 12, 174-179 (2000)).

Of these PDEs, PDE4 is present in various cells, such as airway smooth muscle cells, epithelial cells, inflammatory cells (macrophages, neutrophils and eosinophils) and T cells, and controls cellular functions by regulating intracellular cAMP levels of these cells. On the other hand, other PDEs, such as PDE5, are present, for example, in platelets, cardiac muscle cells and vasculature smooth muscle cells, and by controlling the level of intracellular cGMP or cAMP, they are involved in the management of the circulatory system.

Thus, PDE4 inhibitors are known to exhibit bronchodilator activity, anti-inflammatory activity, mediator release inhibitory activity, immunosuppressive efficacy, and the like, since they inhibit cAMP degradation by PDE4 and thereby induce accumulation of intracellular cAMP.

Thus, agents that specifically inhibit PDE4 are thought not to exhibit the activity of other PDE inhibitors, such as PDE5, in the circulatory system, and are useful in the prevention and / or treatment of various diseases such as inflammatory diseases (e.g., asthma, obstructive pulmonary disease, sepsis, sarcoidosis, nephritis, hepatitis, enteritis, etc.), diabetic diseases, allergic diseases (e.g., allergic rhinitis, allergic conjunctivitis, seasonal conjunctivitis, atopic dermatitis, etc.), autoimmune diseases (e.g., ulcerative colitis, Crohn's disease, rheumatism, psoriasis, multiple sclerosis, osteoporosis, bone fractures, obesity, depression, Parkinson's disease, dementia, ischemic reperfusion injury, leukemia and AIDS (Exp. Opin. Invest. Drugs, 8, 1301-1325 (1999)).

For example, JP-T-8-509731 discloses compounds of formula A as PDE4 inhibitors

(A) wherein R ^1A represents H or C 1-6 alkyl; R ^2A represents C 3-7 alkyl, C 3-7 cycloalkyl, etc .; D ^3A represents COR ^4A , COCOR ^4A , etc .; R ^4A represents H, OR ^5A , NHOH, etc .; R ^5A represents H, C 1-6 alkyl, etc .; X ^A represents O, etc .; Y ^A represents O, etc .; and pharmaceutically acceptable salts thereof, which exhibit PDE4 inhibitory activity (the necessary moieties are cited from the group definitions).

WO93 / 19747 also discloses that compounds of Formula B

(B) wherein R ^1B represents - (CR ^4B R ^5B ) _r BR ^6B ; rB is 1 to 6; R ^4B R ^5B is each independently hydrogen or C 1-2 alkyl; R ^6B represents a hydrogen atom, a C 3-6 cycloalkyl group, etc .; X ^B represents Y ^B R ^2B , etc .; Y ^B represents

O etc .; R ^2B represents methyl, ethyl, etc .; X ^2B represents O, etc .; X ^3B represents a hydrogen atom, etc .; B is 0 to 4; R ^3B represents a hydrogen atom, CN, etc .;

• · • ·

X ^5B represents a hydrogen atom, etc .; Z ^B is CR ^8B R ^8B C (O) OR ^14B, CR ^8B R ^8B C (Y ^'B) NR ^10B R ^14B, etc .; R ^8B represents a hydrogen atom, etc .; R ^10B represents a hydrogen atom, OR ^8B , etc .; ^R14B represents a hydrogen atom, etc .; and pharmaceutically acceptable salts thereof exhibit PDE4 inhibitory activity (the necessary moieties are cited from the group definitions).

WO 93/19749 also discloses that compounds of formula C

(C): wherein ^R1C represents - (CR ^4C R ^5C) _R CR ^6C, etc .; rC is 1 to 6; R ^4C R ^5C is each independently hydrogen or C 1-2 alkyl; ^R6C is hydrogen, C3-6 cycloalkyl, etc .; X ^c represents Y ^C R ^{2 C} , etc .; Y ^c represents 0, etc .; R ^2C represents methyl, ethyl, etc .; X ^{2 C} represents O, etc .; X 3 ^C represents a hydrogen atom, etc .; X 4 ^C represents a group

etc.; R ^3C represents hydrogen, CN, etc .; X ^{5 C} represents a hydrogen atom, etc .; C is 0 to 4; Z ^c represents C (O) OR ^{14 C} , C (Y 1 ^C ) NR 1 ^OC R ^{14 C} , etc .; ^R10C represents a hydrogen atom of ^OR8C , etc .; R ^8C represents a hydrogen atom, etc .; ^R14C is hydrogen, etc .; and pharmaceutically acceptable salts thereof exhibit PDE4 inhibitory activity (the necessary moieties are cited from the group definitions).

In an effort to find compounds with PDE4 inhibitory activity, the inventors have conducted intensive research to find that the Piperidine Compounds of Formula (I) fulfill the objectives of the invention.

SUMMARY OF THE INVENTION

The present invention provides (1) piperidine derivatives of formula (I).

where

R ¹ is 1) hydrogen or 2) cyano;

R ^{2 and} R ³ are each independently 1) C 1-8 alkyl, 2) C 3-7 cycloalkyl, 3) C 1-8 alkyl substituted with C 3-7 cycloalkyl, 4) C 1-8 alkyl substituted with 1 to 3 halogens, 5) hydrogen 6) C 1-8 alkyl substituted with phenyl, 7) C 1-8 alkyl substituted with C 1-8 alkoxy, or 8) a group of formula

wherein n is 1 to 5;

R ^{4 and} R ⁵ are each independently 1) hydrogen or 2) C 1-8 alkyl, or

R ⁴ and R ⁵ are taken together with the carbon atom to which they are attached to form a C 3-7 saturated carbocyclic ring;

R ⁶ is 1) hydroxy, 2) C 1-8 alkoxy, 3) -NHOH, or 4) phenyl substituted C 1-8 alkoxy; and m is 0 or an integer of 1 to 4;

and non-toxic salts thereof;

(2) a method for producing such compounds; and (3) an agent that contains these compounds as an active ingredient.

The following is a more detailed description of the invention.

The C1-8 alkyl groups of formula I include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl and their isomers

The C1-8 alkoxy groups of formula I include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy and their isomers.

As used herein, halogen refers to chlorine, bromine, fluorine or iodine.

C 3-7 cycloalkyl in formula I includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As the C 3-7 saturated carbocyclic ring formed by R ⁴ and R ⁵ , taken together with the carbon atom to which they are attached, C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl- and cyclooctyl

Unless otherwise indicated, all isomers are within the scope of the invention. For example, alkyl, alkoxy and alkylene groups include straight-chain and branched-chain groups. In addition, double bond isomers, rings, fused rings (Ε-, Z-, cis- and trans-isomers), isomers arising from the presence of an asymmetric carbon atom or asymmetric carbon atoms, etc. (R- and S) are included within the scope of the invention. -isomers, a- and / msomers, enantiomers, diastereomers), optically active isomers exhibiting optical rotation (D- and L- or d- and 1-isomers), polar compounds isolated by chromatography (high polarity compounds, low polarity compounds) , equilibrium compounds, mixtures thereof in any proportions and racemic mixtures.

In this text, unless otherwise indicated, the symbol indicates that the bond protrudes below the plane formed by the sheet (that is, the α-configuration), the symbol indicates that the bond protrudes above the plane formed by the sheet (i.e., the β-configuration), the symbol indicates that it is an α-, β-configuration or a mixture thereof and the symbol indicates that it is a mixture of α-configuration and β-configuration.

The compounds of formula I can be converted into non-toxic salts by known methods.

Non-toxic salts of the compounds of the present invention include alkali metal, alkaline earth metal, ammonium, amine, acid addition and the like.

These salts are preferably non-toxic and water soluble. Suitable salts include alkali metal salts (e.g., potassium, sodium, etc.), alkaline earth metal salts (e.g., calcium, magnesium, etc.), ammonium salts, and salts with pharmaceutically acceptable organic amines (e.g., tetramethylammonium, triethylamine, methylamine) , dimethylamine, cyclopentylamine, benzylamine, phenylethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D-glucamine, etc.).

Acid addition salts are preferably non-toxic and water soluble. Suitable acid addition salts include salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate salts; and salts with organic acids such as acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate and gluconate salts.

In addition, the compounds of formula I or their salts can be converted into solvates by known methods.

The solvates are preferably non-toxic and water soluble. Suitable solvates include solvates formed with water and alcoholic solvents (e.g., ethanol, etc.).

In the general formula IR ^{1 is} preferably cyano.

R ² in formula I is preferably C1-8 alkyl, C3-7 cycloalkyl or C1-8 alkyl substituted by C3-7 cycloalkyl, preferably methyl, ethyl, isopropyl, 2-methylpropyl, cyclobutyl, cyclopentyl or cyclopropylmethyl.

Preferably, R ³ in formula I is C 1-8 alkyl, C 1-8 alkyl substituted with 1 to 3 halogen atoms, more preferably methyl, ethyl, isopropyl, 2-methylpropyl or difluoromethyl.

R ⁴ and R ⁵ in formula I are preferably hydrogen.

Preferably, R ⁶ in formula I is hydroxy or -NHOH, more preferably -NHOH.

Of the compounds of the formula I of the present invention, the compounds of formula IA are preferred

R ² ? ^O (IA) wherein all the general symbols are as defined above;

compounds of formula 1B

«· · ·

wherein all the general symbols are as defined above; compounds of formula IC

wherein all the general symbols are as defined above; compounds of formula ID

(ID) wherein all the general symbols are as defined above; compounds of formula (1E)

wherein all the general symbols are as defined above;

compounds of formula 1F

wherein all the general symbols are as defined above; the compounds of formula 1G

wherein all the general symbols are as defined above; compounds of formula 1-H

(1H) wherein all the general symbols are as defined above; the compounds of formula 1J

wherein all the general symbols are as defined above; and compounds of formula 1K

wherein all the general symbols are as defined above.

Particular compounds of the invention include the compounds listed in Tables 1 to 10, the compounds of the Examples and their non-toxic salts, acid addition salts and solvates thereof.

In the tables below, Me represents a methyl group; Et is ethyl; i-Pr represents an isopropyl group; CH ₂ -c-Pr represents cyclopropylmethyl; CH ₂ -c-Pen is cyclopentylmethyl; c-Bu represents cyclobutyl; c-Pen is cyclopentyl; CHF ₂ is difluoromethyl; and the other symbols are as defined above.

• · · ·

(Ι-Α)

R ² R ³ C. R ² R ³ Me Me 33 CH _from c-Pen Me Me Et 34 CH ^ c-Pen Et Me i-Pr 35 CH ^ c-Pen i-Pr Me CH ₂ -c-Pr 36 CH ^ c-Pen CH ₂ -c-Pr Me CH ₂ -c-Pen 37 CH ^ c-Pen CH ₂ -c-Pen Me c-Bu 38 CH _from c-Pen c-Bu Me c-Pen 39 CH ^ c-Pen c-Pen Me chf ₂ 40 CH ^ c-Pen chf ₂ Et Me 41 c-Bu Me Et Et 42 c-Bu Et Et i-Pr 43 c-Bu i-Pr Et CH ₂ -c-Pr 44 c-Bu CH ₂ -c-Pr Et CH ₂ -c-Pen 45 c-Bu CH ₂ -c-Pen Et c-Bu 46 c-Bu c-Bu Et c-Pen 47 c-Bu c-Pen Et chf ₂ 48 c-Bu chf ₂ i-Pr Me 49 c-Pen Me i-Pr Et 50 c-Pen Et i-Pr i-Pr 51 c-Pen i-Pr i-Pr CH ₂ -c-Pr 52 c-Pen CH ₂ -c-Pr i-Pr CH ₂ -c-Pen 53 c-Pen CH ₂ -c-Pen i-Pr c-Bu 54 c-Pen c-Bu i-Pr c-Pen 55 c-Pen c-Pen i-Pr chf ₂ 56 c-Pen chf ₂ CH ₂ -c-Pr Me 57 chf ₂ Me CH ₂ -c-Pr Et 58 chf ₂ Et CH ₂ -c-Pr i-Pr 59 chf ₂ i-Pr CH ₂ -c-Pr CH ₂ -c-Pr 60 chf ₂ CH ₂ -c-Pr CH ₂ -c-Pr CH ₂ -c-Pen 61 chf ₂ CH ₂ -c-Pen CH ₂ -c-Pr c-Bu 62 chf ₂ c-Bu CH ₂ -c-Pr c-Pen 63 chf ₂ c-Pen CH ₂ -c-Pr chf ₂ 64 chf ₂ chf ₂

• · • ·

Table 2

C. R ² R ³ C. R ² R ³ 1 Me Me 33 CH ₂ -c-Pen Me 2 Me Et 34 CH ₂ -c-Pen Et 3 Me i-Pr 35 CH ₂ -c-Pen i-Pr 4 Me CH _from c-Pr 36 CH ₂ -c-Pen CH _from c-Pr 5 Me CH2-c-Pen 37 CH ₂ -c-Pen CH ^ c-Pen 6 Me c-Bu 38 CH ₂ -c-Pen c-Bu 7 Me c-Pen 39 CH ₂ -c-Pen c-Pen 8 Me chf ₂ 40 CH ₂ -c-Pen chf ₂ 9 Et Me 41 c-Bu Me 10 Et Et 42 c-Bu Et 11 Et i-Pr 43 c-Bu i-Pr 12 Et CH 2 c-Pr 44 c-Bu CH 2 c-Pr 13 Et CH ^ c-Pen 45 c-Bu CH ^ c-Pen 14 Et c-Bu 46 c-Bu c-Bu 15 Et c-Pen 47 c-Bu c-Pen 16 Et chf ₂ 48 c-Bu chf ₂ 17 i-Pr Me 49 c-Pen Me 18 i-Pr Et 50 c-Pen Et 19 i-Pr i-Pr 51 c-Pen i-Pr 20 i-Pr CH _from c-Pr 52 c-Pen CH 2 c-Pr 21 i-Pr CH ^ c-Pen 53 c-Pen CH 2-c-Pen 22 i-Pr c-Bu 54 c-Pen c-Bu 23 i-Pr c-Pen 55 c-Pen c-Pen 24 i-Pr chf ₂ 56 c-Pen chf ₂ 25 CH _from c-Pr Me 57 chf ₂ Me 26 CH _from c-Pr Et 58 chf ₂ Et 27 CH 2 c-Pr i-Pr 59 chf ₂ i-Pr 28 CH _from c-Pr CH 2 c-Pr 60 chf ₂ CH _from c-Pr 29 CH _from c-Pr CH _from c-Pen 61 chf ₂ CH _from c-Pen 30 CH 2 c-Pr c-Bu 62 chf ₂ c-Bu 31 CH _r c-Pr c-Pen 63 chf ₂ c-Pen 32 CH _from c-Pr chf ₂ 64 chf ₂ chf ₂

Table 3 Cl-h nc. r? IN

(IC)

C. AND? R ³ C. R ² R ³ 1 Me Me 33 CH _from c-Pen Me 2 Me Et 34 CH2-c-Pen Et 3 Me i-Pr 35 CH ^ c-Peri i-Pr 4 Me CH ₂ -c-Pr 36 CH ^ c-Pen CH _from c-Pr 5 Me CH ₂ -c-Pen 37 CH2-c-Pen CH ^ c-Pen 6 Me c-Bu 38 CH ^ c-Pen c-Bu 1 Me c-Pen 39 CH ^ c-Pen c-Pen 8 Me chf ₂ 40 CH ^ c-Pen chf ₂ 9 Et Me 41 c-Bu Me 10 Et Et 42 c-Bu Et 11 Et i-Pr 43 c-Bu i-Pr 12 Et CH ₂ -c-Pr 44 c-Bu CH 2 c-Pr 13 Et CH ₂ -c-Pen 45 c-Bu CH _Z c-Pen 14 Et c-Bu 46 c-Bu c-Bu 15 Et c-Pen 47 c-Bu c-Pen 16 Et chf ₂ 48 c-Bu chf ₂ 17 i-Pr Me 49 c-Pen Me 18 i-Pr Et 50 c-Pen Et 19 i-Pr i-Pr 51 c-Pen i-Pr 20 i-Pr CH ₂ -c-Pr 52 c-Pen CH 2 c-Pr 21 i-Pr CH ₂ -c-Pen 53 c-Pen CH ^ c-Pen 22 i-Pr c-Bu 54 c-Pen c-Bu 23 i-Pr c-Pen 55 c-Pen c-Pen 24 i-Pr chf ₂ 56 c-Pen chf ₂ 25 CH ₂ -c-Pr Me 57 chf ₂ Me 26 CH ₂ -c-Pr Et 58 chf ₂ Et 27 CH ₂ -c-Pr i-Pr 59 chf ₂ i-Pr 28 CH ₂ -c-Pr CH ₂ -c-Pr 60 chf ₂ CH _r c-Pr 29 CH ₂ -c-Pr CH ₂ -c-Pen 61 chf ₂ CH ^ c-Pen 30 CH ₂ -c-Pr c-Bu 62 chf ₂ c-Bu 31 CH ₂ -c-Pr c-Pen 63 chf ₂ c-Pen 32 CH ₂ -c-Pr chf ₂ 64 chf ₂ chf ₂

Table 4

C. R ² R ³ C. R ² R ³ 1 Me Me 33 CH ₂ -c-Pen Me 2 Me Et 34 CH ₂ -c-Pen Et 3 Me i-Pr 35 CH ₂ -c-Pen i-Pr 4 Me CH _from c-Pr 36 CH ₂ -c-Pen CH _from c-Pr 5 Me CH2-c-Pen 37 CH ₂ -c-Pen CH _from c-Pen 6 Me c-Bu 38 CH ₂ -c-Pen c-Bu 7 Me c-Pen 39 CH ₂ -c-Pen c-Pen 8 Me chf ₂ 40 CH ₂ -c-Pen chf ₂ 9 Et Me 41 c-Bu Me 10 Et Et 42 c-Bu Et 11 Et i-Pr 43 c-Bu i-Pr 12 Et CH _from c-Pr 44 c-Bu CH _from c-Pr 13 Et CH ^ c-Pen 45 c-Bu CH _Z c-Pen 14 Et c-Bu 46 c-Bu c-Bu 15 Et c-Pen 47 c-Bu c-Pen 16 Et chf ₂ 48 c-Bu chf ₂ 17 i-Pr Me 49 c-Pen Me 18 i-Pr Et 50 c-Pen Et 19 i-Pr i-Pr 51 c-Pen i-Pr 20 i-Pr CH _from c-Pr 52 c-Pen CH _from c-Pr 21 i-Pr CH _from c-Pen 53 c-Pen CH _Z c-Pen 22 i-Pr c-Bu 54 c-Pen c-Bu 23 i-Pr c-Pen 55 c-Pen c-Pen 24 i-Pr chf ₂ 56 c-Pen chf ₂ 25 CH _from c-Pr Me 57 chf ₂ Me 26 CH2-c-Pr Et 58 chf ₂ Et 27 CH _from c-Pr i-Pr 59 chf ₂ i-Pr 28 CH _from c-Pr CH _from c-Pr 60 chf ₂ CH _from c-Pr 29 CH _from c-Pr CH 2-c-Pen 61 chf ₂ CH _Z c-Pen 30 CH _from c-Pr c-Bu 62 chf ₂ c-Bu 31 CH 2 c-Pr c-Pen 63 chf ₂ c-Pen 32 CH 2 c-Pr chf ₂ 64 chf ₂ chf ₂

Table 5

O

C. R ² R ³ C. R ² R ³ 1 Me Me 33 CH ₂ -c-Pen Me 2 Me Et 34 CH ₂ -c-Pen Et 3 Me i-Pr 35 CH ₂ -c-Pen i-Pr AND Me CH1-c-Pr 36 CH ₂ -c-Pen CH 2 c-Pr 5 Me CH ^ c-Pen 37 CH ₂ -c-Pen CH 2-c-Pen 6 Me c-Bu 38 CH ₂ -c-Pen c-Bu 7 Me c-Pen 39 CH ₂ -c-Pen c-Pen 8 Me chf ₂ 40 CH ₂ -c-Pen chf ₂ 9 Et Me 41 c-Bu Me 10 Et Et 42 c-Bu Et 11 Et i-Pr 43 c-Bu i-Pr 12 Et CH 2 c-Pr 44 c-Bu CH2-c-Pr 13 Et CH ^ c-Pen 45 c-Bu CH ^ c-Pen 14 Et c-Bu 46 c-Bu c-Bu 15 Et c-Pen 47 c-Bu c-Pen 16 Et chf ₂ 48 c-Bu chf ₂ 17 i-Pr Me 49 c-Pen Me 18 i-Pr Et 50 c-Pen Et 19 i-Pr i-Pr 51 c-Pen i-Pr 20 i-Pr CH _from c-Pr 52 c-Pen CH 2 c-Pr 21 i-Pr CH 2-c-Pen 53 c-Pen CH 2-c-Pen 22 i-Pr c-Bu 54 c-Pen c-Bu 23 i-Pr c-Pen 55 c-Pen c-Pen 24 i-Pr chf ₂ 56 c-Pen chf ₂ 25 CH 2 c-Pr Me 57 chf ₂ Me 26 CH 2 c-Pr Et 58 chf ₂ Et 27 CH 2 c-Pr i-Pr 59 chf ₂ i-Pr 28 CH _from c-Pr CH _from c-Pr 60 chf ₂ CH 2 c-Pr 29 CH 2 c-Pr CH ^ c-Pen 61 chf ₂ CH 2-c-Pen 30 CH 2 c-Pr c-Bu 62 chf ₂ c-Bu 31 CH _from c-Pr c-Pen 63 chf ₂ c-Pen 32 CH 2 c-Pr chf ₂ 64 chf ₂ chf ₂

·· · · · · · · · · · · · · · · · · · · · · ·

Table 6

O

C. R ² R ³ C. R ² R ³ 1 Me Me 33 CH _from c-Pen Me 2 Me Et 34 CH ^ c-Pen Et 3 Me i-Pr 35 CH _Z c-Pen i-Pr 4 Me CH ₂ -c-Pr 36 CH _from c-Pen CH _from c-Pr 5 Me CH ₂ -c-Pen 37 CH ^ c-Pen CH ^ c-Pen 6 Me c-Bu 38 CH ^ c-Pen c-Bu 7 Me c-Pen 39 CH _Z c-Pen c-Pen 8 Me chf ₂ 40 CH ^ c-Pen chf ₂ 9 Et Me 41 c-Bu Me 10 Et Et 42 c-Bu Et 11 Et i-Pr 43 c-Bu i-Pr 12 Et CH ₂ -c-Pr 44 c-Bu CH _from c-Pr 13 Et CH ₂ -c-Pen 45 c-Bu CH _from c-Pen 14 Et c-Bu 46 c-Bu c-Bu 15 Et c-Pen 47 c-Bu c-Pen 16 Et chf ₂ 48 c-Bu chf ₂ 17 i-Pr Me 49 c-Pen Me 18 i-Pr Et 50 c-Pen Et 19 i-Pr i-Pr 51 c-Pen i-Pr 20 i-Pr CH ₂ -c-Pr 52 c-Pen CH _from c-Pr 21 i-Pr CH ₂ -c-Pen 53 c-Pen CH2-c-Pen 22 i-Pr c-Bu 54 c-Pen c-Bu 23 i-Pr c-Pen 55 c-Pen c-Pen 24 i-Pr chf ₂ 56 c-Pen chf ₂ 25 CH _from c-Pr Me 57 chf ₂ Me 26 CH2-c-Pr Et 58 chf ₂ Et 27 CH 2 c-Pr i-Pr 59 chf ₂ i-Pr 28 CH _from c-Pr CH ₂ -c-Pr 60 chf ₂ CH _from c-Pr 29 CH _from c-Pr CH ₂ -c-Pen 61 chf ₂ CH ^ c-Pen 30 CH 2 c-Pr c-Bu 62 chf ₂ c-Bu 31 CH _from c-Pr c-Pen 63 chf ₂ c-Pen 32 CH _from c-Pr chf ₂ 64 chf ₂ chf ₂

• · ·

Table 7 htaC Chh

C. R ² R ³ C. R ² R? 1 Me Me 33 CH ^ c-Peri Me 2 Me Et 34 CH ^ c-Pen Et 3 Me i-Pr 35 CH _from c-Pen i-Pr 4 Me CH ₂ -c-Pr 36 CH ^ c-Pen CH ₂ -c-Pr 5 Me CH ₂ -c-Pen 37 CH ^ c-Pen CH ₂ -c-Pen 6 Me c-Bu 38 CH ^ c-Pen c-Bu 1 Me c-Pen 39 CH _Z c-Pen c-Pen 8 Me chf ₂ 40 CH ^ c-Pen chf ₂ 9 Et Me 41 c-Bu Me 10 Et Et 42 c-Bu Et 11 Et i-Pr 43 c-Bu i-Pr 12 Et CH ₂ -c-Pr 44 c-Bu CH ₂ -c-Pr 13 Et CH ₂ -c-Pen 45 c-Bu CH ₂ -c-Pen 14 Et c-Bu 46 c-Bu c-Bu 15 Et c-Pen 47 c-Bu c-Pen 16 Et chf ₂ 48 c-Bu chf ₂ 17 i-Pr Me 49 c-Pen Me 18 i-Pr Et 50 c-Pen Et 19 i-Pr i-Pr 51 c-Pen i-Pr 20 i-Pr CH ₂ -c-Pr 52 c-Pen CH ₂ -c-Pr 21 i-Pr CH ₂ -c-Pen 53 c-Pen CH ₂ -c-Pen 22 i-Pr c-Bu 54 c-Pen c-Bu 23 i-Pr c-Pen 55 c-Pen c-Pen 24 i-Pr chf ₂ 56 c-Pen chf ₂ 25 CH ₂ -c-Pr Me 57 chf ₂ Me 26 CH ₂ -c-Pr Et 58 chf ₂ Et 27 CH ₂ -c-Pr i-Pr 59 chf ₂ i-Pr 28 CH ₂ -c-Pr CH ₂ -c-Pr 60 chf ₂ CH ₂ -c-Pr 29 CH ₂ -c-Pr CH ₂ -c-Pen 61 chf ₂ CH ₂ -c-Pen 30 CH ₂ -c-Pr c-Bu 62 chf ₂ c-Bu 31 CH ₂ -c-Pr c-Pen 63 chf ₂ c-Pen 32 CH ₂ -c-Pr chf ₂ 64 chf ₂ chf ₂

«·

I 1 • ·

Table 8

HoC CHou ·· fc * fc * · * ♦ * v · · · * · ·

C. R ² R ³ C. R ² R ³ 1 Me Me 33 CH ₂ -c-Pen Me 2 Me Et 34 CH ₂ -c-Pen Et 3 Me i-Pr 35 CH ₂ -c-Pen i-Pr 4 Me CH 2 c-Pr 36 CH ₂ -c-Pen CH ₂ -c-Pr 5 Me CH 2-c-Pen 37 CH ₂ -c-Pen CH ₂ -c-Pen 6 Me c-Bu 38 CH ₂ -c-Pen c-Bu 7 Me c-Pen 39 CH ₂ -c-Pen c-Pen 8 Me chf ₂ 40 CH ₂ -c-Pen chf ₂ 9 Et Me 41 c-Bu Me 10 Et Et 42 c-Bu Et 11 Et i-Pr 43 c-Bu i-Pr 12 Et CH _from c-Pr 44 c-Bu CH ₂ -c-Pr 13 Et CH2-c-Pen 45 c-Bu CH ₂ -c-Pen 14 Et c-Bu 46 c-Bu c-Bu 15 Et c-Pen 47 c-Bu c-Pen 16 Et chf ₂ 48 c-Bu chf ₂ 17 i-Pr Me 49 c-Pen Me 18 i-Pr Et 50 c-Pen Et 19 i-Pr i-Pr 51 c-Pen i-Pr 20 i-Pr CH _of c-Pr 52 c-Pen CH ₂ -c-Pr 21 i-Pr CH ^ c-Pen 53 c-Pen CH ₂ -c-Pen 22 i-Pr c-Bu 54 c-Pen c-Bu 23 i-Pr c-Pen 55 c-Pen c-Pen 24 i-Pr chf ₂ 56 c-Pen chf ₂ 25 CH 2 c-Pr Me 57 chf ₂ Me 26 CH2-c-Pr Et 58 chf ₂ Et 27 CH 2 c-Pr i-Pr 59 chf ₂ i-Pr 28 CH 2 c-Pr CH _from c-Pr 60 chf ₂ CH ₂ -c-Pr 29 CH2-c-Pr CH ^ c-Pen 61 chf ₂ CH ₂ -c-Pen 30 CH _from c-Pr c-Bu 62 chf ₂ c-Bu 31 CH _from c-Pr c-Pen 63 chf ₂ c-Pen 32 CP2-c-Pr chf ₂ 64 chf ₂ chf ₂

• * «

Λ · · · · · · · 4 ·· ··

Table 9

C. R ² R ³ C. R ² R ³ 1 Me Me 33 CH ^ c-Pen Me 2 Me Et 34 CH ^ c-Pen Et 3 Me i-Pr 35 CH ^ c-Pen i-Pr 4 Me CH ₂ -c-Pr 36 CH ^ c-Pen CH ₂ -c-Pr 5 Me CH ₂ -c-Pen 37 CH ^ c-Pen CH ₂ -c-Pen 6 Me c-Bu 38 CH ^ c-Pen c-Bu 7 Me c-Pen 39 CH ^ c-Pen c-Pen 8 Me chf ₂ 40 CH ^ c-Pen chf ₂ 9 Et Me 41 c-Bu Me 10 Et Et 42 c-Bu Et 11 Et i-Pr 43 c-Bu i-Pr 12 Et CH ₂ -c-Pr 44 c-Bu CH ₂ -c-Pr 13 Et CH ₂ -c-Pen 45 c-Bu CH ₂ -c-Pen 14 Et c-Bu 46 c-Bu c-Bu 15 Et c-Pen 47 c-Bu c-Pen 16 Et chf ₂ 48 c-Bu chf ₂ 17 i-Pr Me 49 c-Pen Me 18 i-Pr Et 50 c-Pen Et 19 i-Pr i-Pr 51 c-Pen i-Pr 20 i-Pr CH ₂ -c-Pr 52 c-Pen CH ₂ -c-Pr 21 i-Pr CH ₂ -c-Pen 53 c-Pen CH ₂ -c-Pen 22 i-Pr c-Bu 54 c-Pen c-Bu 23 i-Pr c-Pen 55 c-Pen c-Pen 24 i-Pr chf ₂ 56 c-Pen chf ₂ 25 CH ₂ -c-Pr Me 57 chf ₂ Me 26 CH ₂ -c-Pr Et 58 chf ₂ Et 27 CH ₂ -c-Pr i-Pr 59 chf ₂ i-Pr 28 CH ₂ -c-Pr CH ₂ -c-Pr 60 chf ₂ CH ₂ -c-Pr 29 CH ₂ -c-Pr CH ₂ -c-Pen 61 chf ₂ CH ₂ -c-Pen 30 CH ₂ -c-Pr c-Bu 62 chf ₂ c-Bu 31 CH ₂ -c-Pr c-Pen 63 chf ₂ c-Pen 32 CH ₂ -c-Pr chf ₂ 64 chf ₂ chf ₂

»·· ·· ··

Table 10 y, n

N

NC

Ν 'Y OH

O (IK)

C. R ² R ³ C. R ² R ³ 1 Me Me 33 CH 2-c-Pen Me 2 Me Et 34 CH _from c-Pen Et 3 Me i-Pr 35 CH _rc -Pen i-Pr 4 Me CH ₂ -c-Pr 36 CH2-c-Pen CH _from c-Pr 5 Me CH ₂ -c-Pen 37 CH2-c-Pen CH2-c-Pen 6 Me c-Bu 38 CH 2-c-Pen c-Bu 7 Me c-Pen 39 CH2-c-Pen c-Pen 3 Me chf ₂ 40 CH2-c-Pen chf ₂ 9 Et Me 41 c-Bu Me 10 Et Et 42 c-Bu Et 11 Et i-Pr 43 c-Bu i-Pr 12 Et CH ₂ -c-Pr 44 c-Bu CH _from c-Pr 13 Et CH ₂ -c-Pen 45 c-Bu CH2-c-Pen 14 Et c-Bu 46 c-Bu c-Bu 15 Et c-Pen 47 c-Bu c-Pen 16 Et chf ₂ 48 c-Bu chf ₂ 17 i-Pr Me 49 c-Pen Me 18 i-Pr Et 50 c-Pen Et 19 i-Pr i-Pr 51 c-Pen i-Pr 20 i-Pr CH ₂ -c-Pr 52 c-Pen CH _from c-Pr 21 i-Pr CH ₂ -c-Pen 53 c-Pen CH ^ c-Pen 22 i-Pr c-Bu 54 c-Pen c-Bu 23 i-Pr c-Pen 55 c-Pen c-Pen 24 i-Pr chf ₂ 56 c-Pen chf ₂ 25 CH _from c-Pr Me 57 chf ₂ Me 26 CH 2 c-Pr Et 58 chf ₂ Et 27 CH _from c-Pr i-Pr 59 chf ₂ i-Pr 28 CH _from c-Pr CH ₂ -c-Pr 60 chf ₂ CH 2 c-Pr 29 CH 2 c-Pr CH ₂ -c-Pen 61 chf ₂ CH2-c-Pen 30 CH _from c-Pr c-Bu 62 chf ₂ c-Bu 31 CH1-c-Pr c-Pen 63 chf ₂ c-Pen 32 CH2-c-Pr chf ₂ 64 chf ₂ chf ₂

Next, a method for producing the compounds of the invention is described.

The compounds of the formula I according to the invention can be prepared by the following methods and methods described in the Examples.

[1] Compounds of formula I wherein R ⁶ is C 1-8 alkoxy or C 1-8 alkyl substituted by phenyl; and -OR ² and -OR ^{3 are} not hydroxy, i.e., compounds of Formula IA

⁶ wherein R ^'1 is C 1-8 alkoxy or C 1-8 alkyl substituted phenyl; -OR ² ^'1 and -OR ^3' ¹ have the same meanings as -OR ² and -OR ^3, with the difference that it is not OH; and the other symbols are as defined above; it can be prepared by the following methods a) to c).

a) Compounds of formula IA can be prepared by forming a compound of formula 11-1

wherein all symbols are as defined above; is reacted with a compound of formula II- ^R 4 _of ^R 5

R 1 (CH ₂ ) -C — COR ⁶ · ¹ (III-1) wherein R ⁷ is a leaving group (e.g., halogen, trifluoromethylsulfonyloxy, mesyloxy, or tosyloxy) and other symbols are as defined above.

The reaction of a compound of formula 11-1 with a compound of formula II-1 is known. It is carried out, for example, at 0 to 100 ° C in an inert organic solvent (for example dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile, etc.) in the presence of a base (e.g. potassium carbonate, calcium carbonate, sodium carbonate, cesium carbonate, triethylamine) , pyridine, 2,6-lutidine, etc.).

b) Compounds of formula IA may be prepared by the compound of formula II-2.

wherein all symbols are as defined above; is reacted with a compound of formula II-2

R ⁴ R ⁵

H ₂ N - (CH ₂ ) -V — COR ⁶ ' ¹ ( ^m - ² ) wherein all symbols are as defined above.

Reaction of a compound of formula II-2 with a compound of formula II

III-2 is known. It is carried out, for example, in a mixed solvent consisting of an inert organic solvent (for example dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, dichloroethane, diethyl ether, tetrahydrofuran, acetonitrile, etc.) and acetic acid in the presence of a reducing agent (e.g. sodium triacetoxyborohydride, NaBH (OAc) Sodium 3-cyanoborohydride, (NaBH 3 CN) etc.) at 0 to 100 ° C.

c) Compounds of formula IA wherein m is 1 and each of R ⁴ and R ⁵ is hydrogen, i.e., compounds of formula IA-1

wherein all symbols are as defined above; it can be prepared by reacting a compound of formula 11-1 with a compound of formula IV

H ₂ C = C - COR ⁶ ' ^{1 (IV)}

H where all symbols are as defined above.

Reaction of a compound of formula 11-1 with a compound of formula II

IV is known. For example, it is carried out in an inert organic solvent (e.g. dimethylformamide, dimethylsulfoxide, chloroform, methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile, etc.) in the presence of a base (e.g.

potassium carbonate, calcium carbonate, sodium carbonate, cesium carbonate, triethylamine, pyridine, 2,6-lutidine, etc.) at a temperature of from 0 to 100 ° C.

[2] Compounds of the invention of formula I wherein at least one of -COR ⁶ , -OR ² and -OR ³ is carboxy or hydroxy, i.e. compounds of formula IB

wherein -COR ⁶ ^'2, -OR ^2' ² or -OR ³ ^'2 have the same meanings as -COR ^6, -OR ² and -OR ^3, with the difference that at least one of them represents a carboxyl group or a hydroxyl group; and the other symbols are as defined above; may be prepared by treating a compound of formula IA, prepared as described above, wherein -COR ⁶ ^'1, -OR ^2' ¹ or -OR ³ ^'1 represents a carboxyl group or hydroxyl group protected with a protecting group, i.e. a compound of formula IA-2

wherein -COR ⁶ ^'3, -OR ^2' ³ and -OR ³ ^'3 have the same meanings as -COR ^6, -OR ² and -OR ^3, with the difference that at least one of them represents a carboxyl group or a hydroxyl group protected with a protecting group; and the other symbols are as defined above; subject to a deprotection reaction.

Examples of carboxy protecting groups include methyl, ethyl, tert-butyl and benzyl.

Examples of the hydroxy protecting group include methoxymethyl, 2-tetrahydropyranyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl and benzyl.

However, the list of these carboxy and hydroxy protecting groups is not limiting; other groups can also be used if they can be easily and selectively cleaved. For example, the protecting groups described in TW Greene, Protective Groups in Organic Synthesis, 3rd Edition, Wiley, New York, 1999 may be used.

Deprotection reactions to remove carboxy and hydroxy protecting groups are known, and include (1) alkaline deprotection reaction, (2) acid deprotection reaction, (3) hydrolytic deprotection reaction, (4) deprotection reactions to remove silyl groups and the like

(1) Deprotection reaction under alkaline conditions is, for example, carried out in an organic solvent (e.g. methanol, tetrahydrofuran, dioxane, dimethylformamide, etc.) using an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxide ( for example barium hydroxide, calcium hydroxide, etc.) or a carbonate (e.g., sodium carbonate, potassium carbonate, etc.), an organic amine (e.g., triethylamine, diisopropylethylamine, piperazine, etc.), or a quaternary ammonium salt (e.g., tetrabutylammonium fluoride, etc.) or an aqueous solution thereof or at a temperature of from 0 to 40 ° C.

(2) For example, the deprotection reaction with acidic conditions can be carried out in an organic solvent (e.g. methylene chloride, chloroform, dioxane, ethyl acetate, anisole, etc.) using an organic acid (e.g. acetic acid, trifluoroacetic acid, methanesulfonic acid, etc.), inorganic acid (e.g. hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (e.g., hydrogen bromide / acetic acid, etc.) at a temperature of from 0 to 100 ° C.

(3) For example, the hydrolytic deprotection reaction is carried out in a solvent such as an ether system (e.g. tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), an alcoholic system (e.g. methanol or ethanol), a benzene system (e.g. benzene, toluene, etc.), a ketone system (e.g. acetone, methyl ethyl ketone, etc.), a nitrile system (e.g. acetonitrile, etc.), an amide system (e.g. dimethylformamide etc.), water, ethyl acetate, acetic acid or a mixed solvent containing two or more of the above, in the presence of a catalyst (e.g. palladium on carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.) under normal or elevated pressure under hydrogen or in the presence of ammonium formate at 0 to 200 ° C.

(4) Silyl deprotection reactions are carried out, for example, in a water miscible organic solvent (e.g. tetrahydrofuran, acetonitrile, etc.) using tetrabutylammonium fluoride at 0 to 40 ° C.

• ·

As will be appreciated by those skilled in the art, the compounds of the invention can readily be prepared by the proper application of the above deprotection reactions.

[3] Compounds of the invention of formula I wherein R ⁶ is -NHOH; and -OR ² and -OR ^{3 are} not hydroxy, i.e., compounds of Formula IC

wherein all symbols are as defined above; it is possible to prepare the compound of formula V

wherein R ⁸ represents a hydroxamic acid protecting group; and the other symbols are as defined above; subject to a deprotection reaction.

As the hydroxamic acid protecting group, tert-butyl, -C (CH 3) 2-OCH 3, benzyl, t-butyldimethylsilyl and tetrahydropyran-1-yl can be used, but other groups can be used without limitation, as long as they are readily available. selectively cleaving, for example, those described in TW Greene, Protective Groups in Organic Synthesis, 3rd Edition, Wiley, New York, 1999.

Deprotection reactions to remove these hydroxamic acid protecting groups are known, and include (1) alkaline deprotection reaction, (2) acid deprotection reaction, (3) hydrolytic deprotection reaction, (4) deprotection reaction which remove silyl groups and the like.

These reactions can be carried out by the methods described above.

[4] Compounds of the invention of formula I wherein R ⁶ is a group

-NHOH; and at least one of -OR ² and -OR ³ represents a hydroxy group, i.e. compounds of formula ID

wherein -OR ² ^'4 and -OR ^3' ⁴ have the same meanings as -OR ² and -OR ^3, with the difference that at least one of them is hydroxy; and the other symbols are as defined above; may be prepared by treating a compound of formula IC, prepared as above, in which the -OR ² ^'1 or -OR ^3' ¹ represents a hydroxy group protected with a protecting group, i.e. a compound of formula IC-1

(IC-1) wherein -OR ² ^'5 and -OR ^3' ⁵ have the same meanings as -OR ² and -OR ^3, with the difference that at least one of them represents a hydroxy group protected with a protecting group; and the other symbols are as defined above; subject to a deprotection reaction.

This deprotection reaction can be carried out by the methods described above. The compounds of formulas 11-1, II-2, 111-1, III-2, IV and V are known or can be prepared by known methods.

For example, compounds of formulas 11-1, II-2 and V can be prepared by the methods outlined in Schemes 1 to 3 below.

In these schemes, Me is methyl; Et is ethyl; Boc represents tert-butoxycarbonyl; Ms represents mesyl; LiHMDS represents lithium hexamethyldisilazane; TFA represents trifluoroacetic acid; and the other symbols are as defined above.

«·

Reaction Scheme 1

H, N

R '.2-1

HO ^^ - ^ OH PO (Boc) ₂ O

Boc

I, N.

HO ^ ⁿ ^ OH

MsCl, Et ₃ N

Boc (XI)

R 'i

O, 2-1

Aqueous NaOH, _CO2 H, _CO2 H (VIII)

H ₂ NC (O) NH ₂ o

NH O (IX)

R '1

o _d 3-1 K -Q

2-1

NH

LiAIH,

R '

I o

Ό '»3-1

(Π-1) • · · · · ·

Reaction Scheme 2

CN (ΧΙΠ)

CHO _A CHO (11-2) amidation

CHO

······ ·

· · · · · · · · · · · · · ·

Reaction Scheme 3 tf- ¹

R4 • (CH2-C-COOH

amidation

H2N-OR ⁸ (XVII)

R4 Rs (CHJJm — C — CONHO -tf (V)

In Schemes 1 and 3, compounds which are known or can be prepared by known methods are used as starting compounds of formulas VI, X, XIII and XVII.

In each of the reactions described, the reaction product can be purified by a conventional method, such as distillation under normal or reduced pressure, high performance liquid chromatography, thin layer chromatography, or column chromatography on silica gel or magnesium silicate, washing and recrystallization. Purification can be carried out after each reaction or after several reactions.

The PDE4 inhibitory activity of the compounds of the invention of Formula I is confirmed by the following assays.

In vitro enzymatic assay

U937 cells (derived from human monocytes) are grown in RPMI 1640 medium containing 10% fetal bovine serum, harvested and homogenized in 20 mM Tris-HCl buffer [pH 8.0] containing PMSF (1 mM), leupeptin (1 µg / ml) and pepstatin A (1 µg / ml)]. After centrifugation (at 15,000 min ^-1 for 10 min) the supernatant was separated and filtered through filter 0,45pm. The sample was loaded onto a MonoQ column (Pharmacia, strong anion exchange column) and eluted with a 0 to 0.8 M sodium chloride density gradient. The factions in which •

10 µL of rolipram (selective PDE4 inhibitor) loses PDE activity, is isolated and used as an enzymatic solution for PDE4 inhibitory activity.

The enzyme activity is measured by the following procedure. 80 ml of diluted enzyme solution (in phosphate buffer (pH 7.4) containing 0.1 mg / kg bovine serum albumin), 10 μ \ solution of the compound of the invention in 10% DMSO) and 10 μ \ ³ H-cAMP (20,000 cpm, 10 μΜ) [in imidazole buffer (100 mM, pH 7.5) containing magnesium sulfate (100 mM) and bovine serum albumin (1 mg / ml) are mixed and incubated for 30 minutes at room temperature. The reaction was stopped in the microwave for 2.5 minutes. After centrifugation (2000 min ^-1 for 1 min), 10 µl of snake venom (1 mg / ml, manufactured by Sigma, tradename V7000) is added. The resulting mixture was incubated at room temperature for 30 minutes. Place 50 μΙ of supernatant into the alumina column (100 μΙ). Elution with 80 μ 80 0.005M hydrochloric acid. The radioactivity of the eluate is measured.

The percentage of PDE4 inhibitory activity of the compound of the invention is calculated according to the following equation

Percent 1 - radioactivity in the presence of an inhibitory compound of the invention activity = -x 100 (%) radioactivity in the absence of a compound of the invention

IC 50 values are calculated for each compound as the concentration of the compound of the invention which inhibits 50% of PDE4 activity.

The test results are shown in Table 11.

Table 11

The compound of Example 3 IC50 value (nM) 3 0.03

Activity in TNF-σ production inhibition

A sample of heparinized blood from a healthy person is placed in a 96-well plate at 180 µl / well. To each well, add 10 µl of a solution of the compound of the invention (final concentration in DMSO 0.1% or less) and allow the plate to stand for 30 minutes at 37 ° C in a 5% carbon dioxide incubator. The reaction is initiated by the addition of 10 µL LPS solution. After incubation for 6 hours in a humidified 5% carbon dioxide incubator, the plate is shaken and then centrifuged at 300 xg for 5 minutes to isolate 50 μl of blood plasma. The amount of TNF-α is determined using a human TNF-α ELISA kit (DIACLONE, Cat. No. 850.090.096) according to the attached instructions. The compound of the invention is found to exhibit dose-dependent inhibitory activity.

Toxicity

The toxicity of the compounds of formula (I ') according to the invention is very low so that they can be considered as sufficiently safe for use as a medicament.

Industrial applicability (pharmaceutical application)

Since the compounds of the invention exhibit PDE4 inhibitory activity, they can be considered useful in the prevention and / or treatment of various diseases such as the prevention and / or treatment of various diseases such as inflammatory diseases (e.g., asthma, obstructive opioid diseases, sepsis, sarcoidosis, nephritis) , hepatitis, enteritis, etc.), diabetic diseases, allergic diseases (e.g., allergic rhinitis, allergic conjunctivitis, seasonal conjunctivitis, atopic dermatitis, etc.), autoimmune diseases (e.g., ulcerative colitis, Crohn's disease, rheumatism, psoriasis, multiple sclerosis, collagen diseases, etc. osteoporosis, bone fractures, obesity, depression, Parkinson's disease, dementia, ischemic reperfusion injury, leukemia and AIDS.

For the above purposes, the compounds of the formula I, their non-toxic salts and hydrates of these entities are usually administered systemically or topically, orally or parenterally.

Dosages are determined depending on age, body weight, symptoms, therapeutic effect, route of administration, time of treatment and the like. Usually, an adult human is administered a dose of 1 mg to 1000 mg once or several times per day, or parenterally, 1 mg to 100 mg once. or several times per day or continuously over 1 to 24 hours.

Since the dosage varies depending on various conditions, such as those described above, there are cases in which doses lower or higher than the above ranges may be used.

The compounds of the formula I according to the invention can be administered in the form of solid compositions, liquid compositions and other compositions for oral administration and in the form of injections, lubricants, suppositories, ophthalmic lotions, inhalation and similar formulations for parenteral administration.

Solid compositions for oral administration include tablets, pills, capsules, dispersible powders, granular powders and the like.

Capsules may be hard and soft capsules.

In such solid compositions, the one or more active compounds are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or magnesium silicate-aluminate. The compositions may also contain, in addition to inert diluents, other substances, for example, lubricants, such as magnesium stearate, disintegrants, such as calcium cellulose glycolate; stabilizing agents such as lactose and solubilizers such as glutamic acid and aspartic acid. If desired, the tablets or pills may be coated with gastro- or enteric coatings such as sucrose, gelatin, hydroxypropylcellulose and hydroxypropylcellulose phthalate, or with two or more such coatings. Capsules of absorbable materials such as gelatin are also contemplated.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs, and the like. In such liquid compositions, the one or more active compounds are in solution in a conventional inert diluent (e.g., purified water, ethanol). In addition, such compositions may also contain adjuvants such as wetting or suspending agents, sweetening, flavoring and preservative agents.

Other compositions for oral administration include sprays containing one or more active compounds prepared by conventional methods. Such compositions may contain, in addition to inert diluents, stabilizing agents such as sodium bisulfate, buffering agents for isotonicity, isotonic solutions such as sodium chloride solutions, sodium citrate, or citric acid. Methods for producing sprays are described in U.S. Patent Nos. 2,868,691 and 3,095,355.

As a composition for parenteral injection, sterile aqueous or non-aqueous solutions, suspensions, and emulsions can be used. Aqueous solutions and suspensions contain distilled water for injection and physiological saline. Non-aqueous solutions and suspensions contain propylene glycol, polyethylene glycol, vegetable oil, such as olive oil, alcohols such as ethanol, Polysorbate 80 ^(R) and the like. Sterile aqueous and non-aqueous solutions, suspensions and emulsions can also be used in the form of mixtures. Such compositions may further comprise preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents (e.g., lactose), adjuvants, such as solubilizing aids (e.g., glutamic acid, aparic acid). They can be sterilized by filtration through a bacterial-retaining filter, by incorporating sterilizing agents or by irradiation. They can also be prepared in the form of sterile solid compositions (for example, by lyophilization), which are dissolved in sterile water or other sterile diluents before use.

Dosage forms for instillation parenteral administration include ocular waters, suspension ocular waters, emulsion ocular waters, ophthalmic reconstituted waters, and eye ointments.

These instillation compositions are prepared by known methods. For example, ophthalmic waters can be prepared by selecting, if desired, suitable isotonizing agents (e.g., sodium chloride, concentrated glycerin, etc.), buffering agents (e.g., sodium phosphate, sodium acetate, etc.), surfactants (e.g., Polysorbate80 ^(R)) , polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil, etc.), solubilizing agents (sodium citrate, sodium edetate, etc.), preservatives (e.g., benzalkonium chloride, paraben, etc.) and the like. .

Formulations for inhalation parenteral administration include aerosols, inhalation powders, and inhalation fluids, which may be in a form that dissolves or suspends in use in water or other suitable medium.

These formulations for inhalation can be prepared using known methods.

For example, liquids for inhalation may be prepared by selecting, if desired, suitable preservatives (e.g., benzalkonium chloride, paraben, etc.), coloring agents, buffering agents (e.g., sodium phosphate, sodium acetate, etc.), isotonizing agents (e.g., sodium chloride, concentrated glycerin, etc.), thickeners (e.g., carbovinyl polymer, etc.), absorption aids, and the like.

Inhalation powders can be prepared by selecting, if desired, suitable lubricants (e.g., stearic acid, salts thereof, etc.), binders (e.g., starch, dextrin, etc.), excipients (e.g., lactose, cellulose, etc.), coloring agents, preservatives (e.g., benzalkonium chloride, paraben, etc.), absorption aids, and the like.

Sprays (e.g., aerosol dispensers or nebulizers) are typically used for inhalation fluid delivery. In the case of powders for inhalation, inhalation devices for inhalation of powdered agents are used.

Other compositions for parenteral administration include liquids for external use, topical lubrication, ointments, suppositories for intrarectal administration, pessaries for intravaginal administration, and the like which contain one or more active compounds. These compositions can be prepared by known methods.

»<

• · • ·

Most preferred embodiments of the invention

The invention is further illustrated by the following Comparative Examples and Examples. These examples are merely illustrative and are not intended to limit the invention in any way.

Solvents reported in parentheses are developing or eluting solvents used in chromatographic separations or TLC and solvent ratios are by volume. In the case of NMR, the solvents reported in parentheses are the solvents in which measurements were made.

Comparative Example 1 (tert-Butoxy) -N, N-bis (2-hydroxyethyl) carboxamide

HO 'h ₃ c

Ch ₃ ch ₃

Y

N,

ΌΗ

To a methylene chloride (200 mL) solution of bis (2-hydroxyethyl) amine (20.0 g), a methylene chloride (50 mL) solution of di-tert-butyl dicarbonate (45.6 g) was added dropwise at 0 ° C. The resulting mixture was stirred at 0 ° C for 1.5 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 2 → ethyl acetate alone) to give the title compound (41.0 g) with the following physical properties:

TLC: Rf 0.56 (chloroform: methanol = 10: 1);

NMR (CDCl 3): δ 3.80 (s, 4H), 3.43 (s, 4H), 3.60-3.00 (br, 2H), 1.47 (s, 9H).

Comparative Example 2 (tert-Butoxy) -N, N-bis (2- (methylsulfonyloxy) ethyl) carboxamide

CH,

H, C,

XH,

Οχ / 0 IO, #

IN

H ₃ C ^X Ό

About CH,

Triethylamine (16.0 mL) was added dropwise to the methylene chloride (80 mL) solution of the compound prepared according to Comparative Example 1 (7.85) at -78 ° C.

methanesulfonyl chloride (8.89 mL). The reaction mixture was stirred at -78 ° C for 10 min before water was added. The resulting mixture was warmed to room temperature and extracted with ethyl acetate (2x). The extract was washed with saturated brine. The extract was dried over sodium sulfate and concentrated in vacuo. The title compound (13.2 g) was obtained with the following physical properties

TLC: Rf 0.64 (ethyl acetate);

NMR (CDCl 3): δ 4.40-4.25 (m, 4H), 3.62 (br t, J = 5.4 Hz, 4H), 3.04 (s, 6H), 1.48 (s). , 9H).

Comparative Example 3 4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-ylcarboxylic acid tert-butyl ester

To an anhydrous tetrahydrofuran (30 mL) solution of 2- (3-cyclopentyloxy-4-methoxyphenyl) ethanonitrile (2.50 g), 1.0 M lithium hexamethyldisilazane (LiHMDS, 24.0 mL in tetrahydrofuran) was added dropwise at -78 ° C. The resulting mixture was stirred at -78 ° C for 20 min, then a tetrahydrofuran (10 mL) solution of the compound of Comparative Example 2 was added. The reaction was warmed to room temperature, stirred for 2 h, then diluted with ice water and saturated brine. . The resulting mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (hexane: diethyl ether = 2: 1 → 1: 2 → diethyl ether alone). The title compound (1.78 g) was obtained with the following physical properties

TLC: Rf 0.56 (hexane: ethyl acetate = 2: 1).

Comparative Example 4

4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidine hydrochloride.

• HCl • · · ·

To a methylene chloride (10 mL) solution of the compound prepared according to Comparative Example 3 (1.68 g) was added methyl-thiobenzene (5 mL) and trifluoroacetic acid (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours and then diluted with water. The mixture was extracted with methylene chloride (2x). The extract was dried over anhydrous sodium sulfate and concentrated in vacuo. A 4M solution of hydrogen chloride in ethyl acetate (1 mL) was added to the residue. The resulting mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue and the precipitated solid was filtered off. The title compound (510 mg) is obtained with the following physical properties

TLC: Rf 0.33 (chloroform: methanol = 10: 1);

NMR (CDCl 3): δ 10.02 (br s, 2H), 7.10-7.00 (m, 2H), 6.88 (d, J = 9.0 Hz, 1H), 4.82 (m (1H), 3.86 (s, 3H), 3.80-3.60 (m, 2H), 3.50-3.30 (m, 2H), 2.80-2.60 (m, 2H ), 2.402.20 (m, 2H), 2.10-1.80 (m, 6H), 1.80-1.60 (m, 2H).

Example 1

2- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester

A mixture of the compound prepared according to Comparative Example 4 (300 mg), potassium carbonate (246 mg), dimethylformamide (4 ml) and 2-bromoacetic acid ethyl ester (0.15 ml) was stirred at room temperature for 20 hours. The reaction mixture was then diluted with ethyl acetate and the ethyl acetate mixture was washed with water and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1 → ethyl acetate alone). The title compound (341 mg) was obtained with the following physical properties

TLC: Rf 0.36 (hexane: ethyl acetate = 2: 1);

• ·

I '•

NMR (CDCl ₃ ): δ 7.10-6.95 (m, 2H), 6.86 (d, J = 8.8 Hz, 1H), 4.79 (m, 1H), 4.22 (q , J = 7.0 Hz, 2H), 3.85 (s, 3H), 3.31 (s, 2H), 3.15-3.00 (m, 2H), 2.75-2.55 ( m, 2H), 2.302.05 (m, 2H), 2.20-2.00 (m, 2H), 2.00-1.80 (m, 6H), 1.80-1.50 (m, 2H), 1.30 (t, J = 7.0 Hz, 3H).

Example 1 (1) to Example 1 (14)

The following compounds of the invention were prepared as described in Example 1 using the compound prepared according to Comparative Example 4 or the corresponding amine derivative and ethyl 2-bromoacetic acid or the corresponding halogen derivative.

Example 1 (1)

2- (4- (3,4-Dimethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester

TLC: Rf 0.33 (hexane: ethyl acetate = 2: 1);

NMR (CDCl 3): δ 7.06 (dd, J = 8.4, 2.4 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.87 (d, J =

8.4 Hz, 1H), 4.22 (q, J = 7.4 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.31 (s, 2H) , 3.153.00 (m, 2H), 2.75-2.60 (m, 2H), 2.30-2.15 (m, 2H), 2.15-2.00 (m, 2H), 1 .30 (t, J = 7.4 Hz, 3H).

Example 1 (2)

2- (4- (3-Ethoxy-4-methoxyphenyl-4-cyanopiperidin-1-yl) acetic acid ethyl ester

TLC: Rf 0.50 (ethyl acetate);

NMR (CDCl 3): δ 7.30-6.95 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H) , 4.10 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.31 (s, 2H), 3.13-3.05 (m, 2H), 2, 73-2.60 (m, 2H), 2.26-2.15 (m, 2H), 2.12-2.05 (m, 2H), 1.47 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H).

Example 1 (3)

2- (4- (3-Cyclopropylmethoxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester

TLC: Rf 0.36 (hexane: ethyl acetate = 2: 1);

NMR (CDCl ₃ ): δ 7.05 (dd, J = 8.7, 2.7 Hz, 1H), 6.99 (d, J = 2.7 Hz, 1H), 6.87 (d, J 4.22 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.86 (d, J = 6.9 Hz, 2H), m.p. 3.30 (s, 2H), 3.15-3.00 (m, 2H), 2.75-2.60 (m, 2H), 2.25-2.10 (m, 2H), 2, 15-2.00 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.40-1.20 (m, 1H), 0.70-0.60 (m, 2H), 0.40-0.30 (m, 2H).

Example 1 (4)

2- (4- (3-Isopropyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester

TLC: Rf 0.34 (hexane: ethyl acetate = 2: 1);

NMR (CDCl 3): δ 7.10-7.00 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.54 (sept, J = 6.0 Hz, 1H) 4.22 (q, J = 7.2 Hz, 2H); 3.85 (s, 3H); 3.30 (s, 2H); 3.20-3.00 (m, 2H); 60 (m, 2H), 2.25-2.10 (m, 2H), 2.15-2.00 (m, 2H), 1.37 (d, J = 6.0 Hz, 6H), 1 .30 (t, J = 7.2 Hz, 3H).

Example 1 (5)

2- (4- (3-Cyclobutyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester

H, C

NC

About • · · ·

TLC: Rf 0.95 (chloroform: methanol = 9: 1);

NMR (CDCl 3): δ 7.02-7.00 (m, 1H), 6.90-6.80 (m, 2H), 4.67 (quint, J = 7.2 Hz, 1H), 4, 22 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H), 3.31 (s, 2H), 3.12-3.05 (m, 2H), 2.73-2 60 (m, 2H), 2.55-2.43 (m, 2H), 2.33-2.00 (m, 6H), 1.93-1.78 (m, 1H), 1.76 -1.60 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H).

Example 1 (6)

2- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid ethyl ester

TLC: Rf 0.46 (hexane; ethyl acetate = 2: 1);

NMR (CDCl 3): δ 7.05-6.95 (m, 2H), 6.85 (d, J = 8.7 Hz, 1H), 4.79 (m, 1H), 4.30-4, 15 (m, 2H), 3.84 (s, 3H), 3.37 (q, J = 7.4 Hz, 1H), 3.10-2.95 (m, 2H), 2.90-2 65 (m, 2H), 2.20-2.00 (m, 4H), 2.00-1.80 (m, 6H), 1.75-1.50 (m, 2H), 1.35 (d, J = 7.4 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H).

Example 1 (7)

4- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) butanoic acid ethyl ester

TLC: Rf 0.48 (hexane: ethyl acetate = 2: 3);

NMR (CDCl 3): δ 7.02-6.98 (m, 2H), 6.87-6.84 (m, 1H), 4.83-4.76 (m, 1H), 4.15 (q , J =

7.2 Hz, 2H), 3.85 (s, 3H), 3.05-2.97 (m, 2H), 2.52-2.43 (m, 4H), 2.36 (t, J). 7.22, 2H), 2.12-2.03 (m, 4H), 2.01-1.76 (m, 8H), 1.68-1.55 (m, 2H), 1, 27 (t, J = 7.2 Hz, 3H).

Example 1 (8) • · • · ·

2- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) butanoic acid ethyl ester

TLC: Rf 0.55 (hexane: ethyl acetate = 2: 1);

NMR (CDCl 3): δ 7.02-6.98 (m, 2H), 6.88-6.83 (m, 1H), 4.83-4.76 (m, 1H), 4.24 (q , J =

7.4 Hz, 2H), 3.84 (s, 3H), 3.16-3.10 (m, 1H), 3.05-2.95 (m, 2H), 2.95-2.84 (m, 1H), 2.79-2.69 (m, 1H), 2.13-2.01 (m, 4H), 2.00-1.54 (m, 10H), 1.26 (t). J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H).

Example 1 (9)

2- (4- (3-Cyclopentyloxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester

TLC: Rf 0.20 (hexane: ethyl acetate = 2: 1);

NMR (CDCl 3): δ 7.16 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.03 (dd, J = 8.4,

2.4 Hz, 1H), 6.54 (t, J = 75.3 Hz, 1H), 4.83 (m, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3 31 (s, 2H), 3.20-3.00 (m, 2H), 2.80-2.60 (m, 2H), 2.30-2.10 (m, 2H), 2.15. -2.00 (m, 2H), 2.00-1.70 (m, 6H), 1.70-1.55 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H ).

Example 1 (10)

2- (4- (3-Cyclopentyloxy-4-ethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester •

XH,

O

TLC: Rf 0.80 (chloroform: methanol = 10: 1);

NMR (CDCl 3): δ 7.05-6.95 (m, 2H), 6.86 (d, J = 9.0 Hz, 1H), 4.78 (m, 1H), 4.22 (q, 2 H). J = 7.2 Hz, 2H), 4.06 (q, J = 7.2 Hz, 2H), 3.30 (s, 2H), 3.10-3.00 (m, 2H), 2, 75-2.60 (m, 2H), 2.25-2.10 (m, 2H), 2.15-2.00 (m, 2H), 1.95-1.75 (m, 6H), 1.70-1.55 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H).

Example 1 (11)

2- (4- (3-Cyclopentyloxy-4-ethoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid ethyl ester

TLC: Rf 0.41 (hexane: ethyl acetate = 2: 1);

NMR (CDCl 3): δ 7.05-6.95 (m, 2H), 6.86 (d, J = 9.0 Hz, 1H), 4.78 (m, 1H), 4.30-4, 15 (m, 2H), 4.05 (q, J = 6.9 Hz, 2H), 3.36 (q, J = 6.9 Hz, 1H), 3.10-2.95 (m, 2H) ), 2.922.65 (m, 2H), 2.20-2.00 (m, 4H), 2.00-1.80 (m, 6H), 1.70-1.50 (m, 2H), 1.42 (t, J = 6.9 Hz, 3H), 1.34 (d, J = 6.9 Hz, 3H), 1.32 (t, J = 6.9 Hz, 3H).

Example 1 (12)

2- (4- (3-Cyclopentyloxy-4-isopropyloxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester

.........

TLC: Rf 0.87 (chloroform: methanol = 9: 1);

NMR (CDCl ₃ ): δ 7.01-6.97 (m, 2H), 6.89 (d, J = 7.8 Hz, 1H), 4.80-4.74 (m, 1H), 4 , 42 (sept, J = 6.0 Hz, 1H), 4.22 (q, J = 7.0 Hz, 2H), 3.30 (s, 2H), 3.12-3.02 (m, 2H), 2.722.61 (m, 2H), 2.26-2.14 (m, 2H), 2.12-2.05 (m, 2H), 1.90-1.75 (m, 2H) , 1.65-1.50 (m, 6H), 1.31 (d, J = 6.0 Hz, 6H), 1.28 (t, J = 7.0 Hz, 3H).

Example 1 (13)

2- (4- (3-Isopropyloxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester

TLC: Rf 0.63 (hexane: ethyl acetate = 1: 3);

NMR (CDCl 3): δ 7.17 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 7.05 (dd, J = 8.4,

2.3 Hz, 1 H), 6.57 (t, J = 75.5 Hz, 1H), 4.58 (sept, J = 6.1 Hz, 1H), 4.22 (q, J = 7, 2 Hz, 2H), 3.31 (s, 2H), 3.14-3.06 (m, 2H), 2.73-2.63 (m, 2H), 2.26-2.15 (m (2H), 2.21-2.04 (m, 2H), 1.37 (d, J = 6.1 Hz, 6H), 1.30 (t, J = 7.2 Hz, 3H).

Example 1 (14)

2- (4- (3-Cyclohexyloxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester

TLC: Rf 0.53 (hexane: ethyl acetate = 1: 1);

NMR (CDCl 3): δ 7.17 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 7.06 (dd, J = 8.6,

2.3 Hz, 1H), 6.58 (t, J = 75.5 Hz, 1H), 4.31 (m, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3 31 (s, 2H), 3.13-3.06 (m, 2H), 2.72-2.63 (m, 2H), 2.25-2.15 (m, 2H), 2.12 -2.03 (m, 2H), 1.99-1.89 (m, 2H), 1.85-1.72 (m, 2H), 1.66-1.50 (m, 2H), 1 , 50-1.23 (m, 4H), 1.28 (t, J = 7.2 Hz, 3H).

• 4

• · · ·

Example 2

2- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

A mixture of the compound prepared according to Example 1 (330 mg), ethanol (5 ml) and 2M aqueous sodium hydroxide solution (0.86 ml) was stirred at room temperature for 35 minutes. The reaction mixture was then neutralized with 2M hydrochloric acid (0.86 mL) and azeotroped with toluene. The residue was purified by silica gel column chromatography (chloroform: methanol: water = 10: 2: 0.1). The compound of the invention (278 mg) was obtained with the following physical properties

TLC: Rf 0.22 (chloroform: methanol: acetic acid = 10: 1: 0.2);

NMR (CDCl 3): δ 7.10-7.00 (m, 2H), 6.88 (d, J = 9.0 Hz, 1H), 4.83 (m, 1H), 4.30-4, 00 (br, 1H), 3.85 (s, 3H), 3.56 (br d, J = 12.6 Hz, 2H), 3.46 (s, 2H), 2.99 (br t, J) = 12.6 Hz, 2H), 2.51 (br t, J = 12.6 Hz, 2H), 2.19 (br d, J = 12.6 Hz, 2H), 2.05-1.75 (m, 6H), 1.70-1.55 (m, 2H).

Example 2 (1) to Example 2 (14)

The following compounds of the invention were obtained in the same manner as described in Example 2 but using the compounds prepared according to Examples 1 (1) to 1 (14) instead of the compound prepared according to Example 1.

Example 2 (1)

2- (4- (3,4-Dimethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.38 (chloroform: methanol: acetic acid = 10: 2: 1);

NMR (DMSO-d 6): δ 7.10-7.00 (m, 2H), 6.97 (d, J = 9.3 Hz, 1H), 3.78 (s, 3H), 3.75 ( with,

3H), 4.00-3.00 (br, 1H), 3.23 (s, 2H), 3.05-2.95 (m, 2H), 2.65-2.50 (m, 2H) , 2.20-1.95 (m, 4H).

• · 4 «> 4 • ·

Example 2 (2)

2- (4- (3-Ethoxy-4-methoxyphenyl-4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.30 (chloroform: methanol = 9: 1);

NMR (CDCl 3): δ 7.10-7.05 (m, 2H), 6.95-6.85 (m, 1H), 4.15 (q, J = 6.9 Hz, 2H), 3, 88 (s, 3H), 3.50-3.40 (m, 4H), 3.10-2.95 (m, 2H), 2.60-2.40 (m, 3H), 2.25- 2.15 (m, 2H), 1.49 (t, J = 6.9 Hz, 3H).

Example 2 (3)

2- (4- (3-Cyclopropylmethoxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.59 (chloroform: methanol: acetic acid = 10: 2: 1);

NMR (DMSO-d 6): δ 7.05-6.95 (m, 3H), 3.83 (d, J = 6.9 Hz, 2H), 3.76 (s, 3H), 3.602.90 ( br, 1H), 3.27 (s, 2H), 3.05-2.95 (m, 2H), 2.70-2.50 (m, 2H), 2.20-1.95 (m, 4H), 1.20 (m, 1H), 0.65-0.55 (m, 2H), 0.40-0.25 (m, 2H).

Example 2 (4)

2- (4- (3-Isopropyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.10 (ethyl acetate);

NMR (CDCl 3): δ 7.15-7.00 (m, 2H), 6.95-6.85 (m, 1H), 4.59 (sept, J = 6.0 Hz, 1H),

3.86 (s, 3H), 3.60-3.50 (m, 2H), 3.46 (s, 2H), 3.05-2.93 (m, 2H), 2.85-2, 60 (m, 1 H),

2.60-2.40 (m, 2H), 2.24-2.12 (m, 2H), 1.37 (d, J = 6.0 Hz, 6H).

* fc

Example 2 (5)

2- (4- (3-Cyclobutyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.10 (ethyl acetate);

NMR (CDCl ₃ ): δ 7.10-7.00 (m, 1H), 6.95-6.85 (m, 2H), 4.71 (quint, J = 7.5 Hz, 1H), 3 87 (s, 3H), 3.70-3.40 (m, 2H), 3.49 (s, 2H), 3.10-2.95 (m, 2H), 2.70-2.00 (m, 9H), 2.00-1.80 (m, 1H), 1.80-1.60 (m, 1H).

Example 2 (6)

2- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid

TLC: Rf 0.67 (chloroform: methanol: acetic acid = 15: 2: 1);

NMR (DMSO-d 6) 7.03-6.94 (m, 3H), 4.88-4.80 (m, 1H), 3.73 (s, 3H), 3.30 (q, J = 7 , 1 Hz, 1H), 4.00-2.70 (br, 1H), 3.00-2.90 (m, 2H), 2.78-2.68 (m, 1H), 2.66- 2.56 (m, 1H), 2.13-2.04 (m, 2H), 2.02-1.80 (m, 4H), 1.76-1.63 (m, 4H), 1, 63-1.50 (m, 2H), 1.19 (d, J = 7.1 Hz, 3H).

Example 2 (7)

4- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl)) butanoic acid

TLC; Rf 0.55 (chloroform: methanol = 8: 1);

NMR (DMSO-d 6): δ 7.03-6.94 (m, 3H), 4.87-4.81 (m, 1H), 3.74 (s, 3H), 3.31 (br, 1H) ), 3.01-2.96 (m, 2H), 2.44-2.38 (m, 2H), 2.33-2.21 (m, 4H), 2.13-2.08 (m , 2H), 2.00-1.94 (m, 2H), 1.92-1.83 (m, 2H), 1.76-1.63 (m, 6H), 1.62-1, 54 (m, 2H).

Example 2 (8)

2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl)) butanoic acid

TLC: Rf 0.52 (chloroform: methanol = 9: 1);

NMR (DMSO-d 6): δ 7.02-6.93 (m, 3H), 4.87-4.80 (m, 1H), 3.72 (s, 3H), 3.31 (br, 1H) ), 3.05 (t, J = 7.4 Hz, 1H), 2.97-2.86 (m, 2H), 2.81-2.70 (m, 1H), 2.64-2, 54 (m, 1H), 2.13-2.04 (m, 2H), 1.99-1.80 (m, 4H), 1.75-1.63 (m, 6H), 1.63- 1.51 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H).

Example 2 (9)

2- (4- (3-Cyclopentyloxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.35 (chloroform: methanol: acetic acid = 10: 1: 0.2);

NMR (DMSO-d ₆ ): δ 7.25-7.15 (m, 2H), 7.09 (dd, J = 8.1, 2.1 Hz, 1H), 7.01 (t, J = 75.0 Hz, 1H), 4.98 (m, 1H), 3.60-3.00 (br, 1H), 3.26 (s, 2H), 3.10-2.95 (m, 2H) 2.70-2.50 (m, 2H), 2.20-2.00 (m, 4H), 2.00-1.80 (m, 2H), 1.80-1.60 (m, 4H), 1.65-1.50 (m 2H).

Example 2 (10)

2- (4- (3-Cyclopentyloxy-4-ethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.39 (chloroform: methanol: acetic acid = 10: 1: 0.2);

NMR (DMSO-d 6): δ 7.05-6.90 (m, 3H), 4.83 (m, 1H), 4.00 (q, J = 6.9 Hz, 2H), 4.003.00 ( br, 1H), 3.23 (s, 2H), 3.05-2.95 (m, 2H), 2.65-2.50 (m, 2H), 2.15-1.90 (m, 4H), 1.95-1.80 (m, 2H), 1.80-1.60 (m, 4H), 1.65-1.50 (m, 2H), 1.29 (t, J = 6.9 Hz, 3H).

Example 2 (11)

2- (4- (3-Cyclopentyloxy-4-ethoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid

TLC: Rf 0.47 (chloroform: methanol: acetic acid = 10: 1: 0.2);

NMR (DMSO-d 6): δ 7.05-6.90 (m, 3H), 4.83 (m, 1H), 3.99 (q, J = 6.9 Hz, 2H), 3.903.00 ( br, 1H), 3.31 (q, J = 6.9 Hz, 1H), 3.05-2.85 (m, 2H), 2.73 (m, 1H), 2.61 (m, 1H) ), 2.15-2.00 (m, 2H), 2.05-1.80 (m, 4H), 1.80-1.60 (m, 4H), 1.65-1.50 (m (2H), 1.29 (t, J = 6.9 Hz, 3H), 1.19 (d, J = 6.9 Hz, 3H).

Example 2 (12)

2- (4- (3-Cyclopentyloxy-4-isopropyloxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.20 (chloroform: methanol = 9: 1);

NMR (CDCl 3): δ 7.04 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.4, 2.1 Hz, 1H), 6.91 (d, J =

8.4 Hz, 1H), 4.84-4.78 (m, 1H), 4.44 (sept, J = 6.0 Hz, 1H), 3.48-3.34 (m, 4H), 3.02

2.90 (m, 2H), 2.48-2.30 (m, 2H), 2.20-1.75 (m, 9H), 1.70-1.60 (m, 2H), 1, 32 (d, j =

6.0 Hz, 6H).

Example 2 (13)

2- (4- (3-Isopropyloxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.35 (chloroform: methanol: acetic acid = 10: 2: 1);

NMR (DMSO-d ₆ ): δ 7.25 (d, J = 2.2 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.11 (dd, J =

8.4, 2.2 Hz, 1H), 7.04 (t, J = 74.6 Hz, 1H), 4.74 (sept, J = 5.9 Hz, 1H), 3.31 (br, 1 H), 3.23 (s, 2H), 3.05-2.98 (m, 2H), 2.63-2.53 (m, 2H), 2.14-1.98 (m, 4H) , 1.28 (d, J = 5.9 Hz, 6H).

Example 2 (14)

2- (4- (3-Cyclohexyloxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.50 (chloroform: methanol: acetic acid = 10: 2: 1);

NMR (DMSO-d 6): δ 7.26 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.10 (dd, J =

8.5, 2.1 Hz, 1H), 7.03 (t, J = 74.6 Hz, 1H), 4.52 (m, 1H), 3.33 (br, 1H), 3.19 ( s, 2H), 3.06-2.97 (m, 2H), 2.61-2.50 (m, 2H), 2.15-1.98 (m, 4H), 1.93-1, 82 (m, 2H), 1.75-1.64 (m, 2H), 1.55-1.25 (m, 6H).

• ·

Comparative Example 5

N- (1-Methyl-1-methoxyethyl) -2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetamide

Example 2 compound 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC; 192 mg), 1-hydroxybenzotriazole (HOBt; 135 mg), dimethylformamide (4 mL) and (1-methoxy-1-methylethyl) oxyamine (0.35 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water (2x), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate alone). The title compound (289 mg) is obtained with the following physical properties

TLC: Rf 0.26 (ethyl acetate);

NMR (CDCl 3): δ 8.94 (br s, 1H), 7.05-6.90 (m, 2H), 6.87 (d, J = 8.4 Hz, 1Η), 4.81 (m (1H), 3.86 (s, 3H), 3.36 (s, 3H), 3.23 (s, 2H), 3.10-3.00 (m, 2H), 2.80-2, 65 (m, 2H), 2.20-2.00 (m, 2H), 2.10-1.75 (m, 8H), 1.70-1.55 (m, 2Η), 1.46 ( s, 6H).

Example 3

N-Hydroxy-2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyano-piperidin-1-yl) acetamide hydrochloride

A mixture of the compound prepared according to Comparative Example 5, methanol (3 ml) and 2M hydrochloric acid (0.35 ml) was stirred at room temperature for 1 hour.

The reaction mixture was azeotroped with toluene. The residue is triturated and filtered using isopropyl ether and a small amount of methanol. The compound of the invention (189 mg) with the following physical properties was obtained.

TLC: Rf 0.38 (chloroform: methanol = 10: 1);

NMR (pyridine-ds + CDCl 3): δ 7.09 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.4, 2.4 Hz, 1H), 6.88 ( d, J = 8.4 Hz, 1H), 6.08 (br s, 3H), 4.75 (m, 1H), 3.72 (s, 3H), 3.30 (s, 2H), 3 , 02 (br d, J = 14.4 Hz, 2H), 2.75-2.60 (m, 2H), 2.20-1.95 (m, 4H), 2.00-1.65 ( m, 6H),

1.60-1.40 (m, 2H).

Example 4 to Example 4 (11)

The following compounds of the invention were obtained in the same manner as described in Comparative Example 5-Example 3 using the compound prepared according to Example 2 (1) to 2 (12) instead of the compound prepared according to Example 2.

Example 4

N-Hydroxy-2- (4- (3,4-dimethoxyphenyl) -4-cyanopiperidin-1-yl) acetamide hydrochloride

H

TLC: Rf 0.21 (chloroform: methanol = 10: 1);

NMR (pyridine-ds + CDCl 3): δ 7.05-6.95 (m, 2H), 6.85 (d, J = 9.0 Hz, 1H), 6.80-6.00 (br, 3H ), 3.75 (s, 6H), 3.28 (s, 2H), 3.05-2.95 (m, 2H), 2.70-2.55 (m, 2H), 2.20- 1.90 (m, 4H).

Example 4 (1)

N-Hydroxy-2- (4- (3-ethoxy-4-methoxyphenyl-4-cyanopiperidine-1-)

-yl) acetamide h ₃ c ^ CL ^NCx X H ^{'χ Ν} ^{/ Χ γ'} ^{Ν ΟΗ} O • HCl TLC: Rf 0.15 (ethyl acetate); NMR (pyridine-ds + CDCl 3) 8.30-7.00 (m, 5H), 6.93-6.87 (m, 1H), 3.95 (q, J)

2H), 3.74 (s, 3H), 3.34 (s, 2H), 3.10-3.00 (m, 2H), 2.75-2.60 (m, 2H), 2.15 -1.95 (m, 4H), 1.33 (t, J = 6.9 Hz, 3H).

• ·

Example 4 (2)

N-Hydroxy-2- (4- (3-cyclopropylmethoxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetamide hydrochloride

TLC: Rf 0.31 (chloroform: methanol = 10: 1);

NMR (pyridine-ds + CDCl 3): δ 8.80-7.50 (br, 3H), 7.08 (d, J = 2.4 Hz, 1H), 7.02 (dd, J =

8.4, 2.4 Hz, 1H); 6.87 (d, J = 8.4 Hz, 1H); 3.83 (d, J = 6.9 Hz, 2H); 3H), 3.30 (s, 2H), 3.10-2.90 (m, 2H), 2.70-2.55 (m, 2H), 2.15-1.95 (m, 4H) 1.26 (m, 1H); 0.550.45 (m, 2H); 0.35-0.25 (m, 2H).

Example 4 (3)

N-Hydroxy-2- (4- (3-isopropyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetamide hydrochloride

TLC: Rf 0.22 (ethyl acetate);

NMR (pyridine-ds + CDCl 3): δ 7.10 (d, J = 2.1 Hz, 1H), 7.02 (dd, J = 6.0, 2.1 Hz, 1H), 6.88 ( d, J = 6.0 Hz, 1H), 6.25-5.50 (m, 3H), 4.51 (sept, J = 6.0 Hz, 1H), 3.73 (s, 3H), 3.28 (s, 2H), 3.05-2.95 (m, 2H), 2.75-2.55 (m, 2H), 2.15-1.95 (m, 4H), 1, 28 (d, J = 6.0 Hz, 6H).

Example 4 (4)

N-Hydroxy-2- (4- (3-cyclobutyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetamide hydrochloride • · · ·

TLC: Rf 0.20 (ethyl acetate);

NMR (pyridine-d ₅ + CDCl ₃ ): δ 7.05-7.00 (m, 2H), 6.95-6.88 (m, 1H), 6.80-6.20 (m, 3H) , 4.65 (quint, J = 6.9 Hz, 1H), 3.75 (s, 3H), 3.36 (s, 2H), 3.10-3.00 (m, 2H), 2, 75-2.65 (m, 2H), 2.40-2.30 (m, 2H), 2.20-1.90 (m, 6H), 1.75-1.40 (m, 2H).

Example 4 (5)

N-Hydroxy-2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanamide hydrochloride

TLC: Rf 0.44 (chloroform: methanol = 10: 1);

NMR (pyridine-ds + CDCl 3): δ 7.20 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 8.3, 2.3 Hz, 1H), 6.94 ( d, J = 8.3 Hz, 1H), 6.45 (br, 3H), 4.82-4.75 (m, 1H), 3.74 (s, 3H), 3.53 (q, J) =

6.9 Hz, 1H), 3.23-3.02 (m, 3H), 2.93-2.82 (m, 1H), 2.26-2.10 (m, 4H), 1.95 -1.65 (m, 6H), 1.53-1.41 (m, 2H), 1.47 (d, J = 6.9 Hz, 3H).

Example 4 (6)

N-Hydroxy-4- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) butanamide hydrochloride

TLC: Rf 0.63 (chloroform: methanol = 9: 1);

• ·

NMR (pyridine-ds + CDCl ₃ ): δ 7.29 (d, J = 2.6 Hz, 1H), 7.17 (dd, J = 8.7, 2.6 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 6.04 (br, 3H), 4.89-4.83 (m, 1H), 3.72 (s, 3H), 3.32-3, 28 (m, 2H), 2.90-2.63 (.delta., 6H), 2.46 (t, J = 6.9 Hz, 2H), 2.26-2.14 (m, 4H), 1 , 92-1.85 (m, 4H), 1.80-1.66 (m, 2H), 1.56-1.45 (m, 2H).

Example I ad 4 (7)

N-Hydroxy-2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) butanamide hydrochloride

TLC: Rf 0.54 (chloroform: methanol = 9: 1);

NMR (pyridine-ds + CDCl 3): δ 7.20 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 8.5, 2.4 Hz, 1H), 6.92 ( d, J = 8.5 Hz, 1H), 6.35 (br, 3H), 4.83-4.76 (m, 1H), 3.72 (s, 3H), 3.34-3.15 (m, 4H), 3.06-2.96 (m, 1H), 2.27-2.00 (m, 5H), 1.95-1, 62 (m, 7H), 1.54-1 39 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).

Example 4 (8)

N-Hydroxy-2- (4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetamide hydrochloride

TLC: Rf 0.36 (chloroform: methanol = 10: 1);

NMR (pyridine-ds + CDCl 3): δ 7.23 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 8.4, 1.8 Hz, 1H), 6.97 (t, J = 75.0 Hz, 1H), 6.60-5.60 (br, 3H), 4.74 (m, 1H), 3.31 (s, 2H), 3.10-3.00 (m, 2H), 2.70-2.60 (m, 2H), 2.20-2.00 (m, 4H), 1, 85-1.60 (m, 6H), 1.60-1.40 (m, 2H).

• ·

Example 4 (9)

N-Hydroxy-2- (4- (3-cyclopentyloxy-4-ethoxyphenyl) -4-cyanopiperidin-1-yl) acetamide hydrochloride

TLC: Rf 0.36 (chloroform: methanol = 10: 1);

NMR (pyridine-ds + CDCl 3): δ 8.10-7.20 (br, 3H), 7.10 (d, J = 2.1 Hz, 1H), 7.00 (dd, J =

8.4, 2.1 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.76 (m, 1H), 3.97 (q, J = 6.9 Hz, 2H), 3.31 (s, 2H), 3.10-2.95 (m, 2H), 2.75-2.60 (m, 2H), 2.20-1.95 (m, 4H) , 2.00-1.65 (m, 6H),

1.60-1.40 (m, 2H), 1.31 (t, J = 6.9 Hz, 3H).

Example 4 (10)

N-Hydroxy-2- (4- (3-cyclopentyloxy-4-ethoxyphenyl) -4-cyanopiperidin-1-yl) propanamide hydrochloride

TLC: Rf 0.37 (chloroform: methanol = 10: 1);

NMR (pyridine-ds + CDCl 3): δ 7.14 (br s, 1H), 7.03 (br d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 7.30-6.60 (br, 3H), 4.77 (m, 1H), 3.97 (q, J = 7.2 Hz, 2H), 3.42 (m, 1H),

3.15-3.00 (m, 2H), 2.96 (m, 1H), 2.77 (m, 1H), 2.20-2.00 (m, 4H), 2.00-1, 60 (m, 6H),

1.60-1.40 (m, 2H), 1.42 (d, J = 6.6 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H).

• · • ·

Example 4 (1 1)

N-Hydroxy-2- (4- (3-cyclopentyloxy-4-isopropyloxyphenyl) -4-cyanopiperidin-1-yl) acetamide hydrochloride

ΌΗ

TLC: Rf 0.40 (chloroform: methanol = 9: 1);

NMR (pyridine-dg + CDCl 3): δ 7.15-7.10 (m, 1H), 7.05-6.90 (m, 2H), 5.80-5.35 (m, 3H), 4 , 78-4.72 (m, 1H), 4.46 (sept, J = 6.0 Hz, 1H), 3.28 (s, 2H), 3.04-2.96 (m, 2H), 2.82.58 (m, 2H), 2.15-1.95 (m, 4H), 1.95-1.65 (m, 6H), 1.58-1.45 (m, 2H), 1, 28 (d, J = 6.0 Hz, 6H).

Example 5

3- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid methyl ester

To a tetrahydrofuran (5 mL) solution of the compound of Comparative Example 4 (0.45 g) was added triethylamine (0.37 mL) and methyl acrylate (0.36 mL). The resulting mixture was stirred at 45 ° C for 1 day, then cooled to room temperature and poured into water. The aqueous mixture was extracted with ethyl acetate. The extract was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1). The compound of the invention (0.4505 g) was obtained with the following physical properties

TLC: Rf 0.42 (hexane: ethyl acetate = 2: 3);

NMR (CDCl 3): δ 7.02-6.97 (m, 2H), 6.87-6.83 (m, 1H), 4.83-4.76 (m, 1H), 3.85 (s). ,

3H), 3.70 (s, 3H), 3.05-2.96 (m, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.59-2.49 (m , 2H), 2.55 (t, J = 7.2 Hz, 2H), 2.12-2.02 (m, 4H), 2.02-1.76 (m, 6H), 1.70- 1.50 (m, 2H).

cc · · · · · · ····································

Example 6

(2R) -2- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid methyl ester

(S) - (-) - Methyl lactate (0.34 mL) was dissolved in methylene chloride (3 mL) under argon at 0 ° C. Anhydrous trifluoromethanesulfonic acid (0.661 mL) and 2,6-lutidine (0.457 mL) were added to the solution. The reaction mixture was stirred at room temperature for 30 minutes and then a methylene chloride (2.5 mL) solution of the compound of Comparative Example 4 (400 mg) followed by triethylamine (0.358 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, then water (5 mL) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (5 mL x 3). The extract is combined with the organic layer. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1). The compound of the invention (492 mg) was obtained with the following physical properties

TLC: Rf 0.90 (chloroform: methanol = 9: 1);

NMR (CDCl 3): δ 7.05-6.97 (m, 2H), 6.87-6.83 (m, 1H), 4.85-4.75 (m, 1H), 3.84 (s). , 3H), 3.76 (s, 3H), 3.39 (q, J = 7.0 Hz, 1H), 3.10-2.95 (m, 2H), 2.85-2.68 ( m, 2H),

2.15-2.05 (m, 4H), 2.00-1.75 (m, 6H), 1.65-1.45 (m, 2H), 1.35 (d, J = 7.0 Hz, 3H).

Example 6 (1)

(2S) -2- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid methyl ester

By the method described in Example 6, using the (R) - (+) - methyl lactate instead of (S) - (-) - methyl lactate, a compound of the invention having the following physical properties is prepared.

TLC: Rf 0.90 (chloroform: methanol = 9: 1);

Example 7 to Example 7 (2)

The following compounds of the invention were prepared in the same manner as described in Example 2 using the compound prepared in Example 5, Example 6 or Example 6 (1) instead of the compound prepared according to Example 1.

Example 7

3- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid

TLC: Rf 0.43 (chloroform: methanol = 9: 1);

NMR (DMSO-d ₆ ): δ 7.03-6.95 (m, 3H), 4.87-4.80 (m, 1H), 3.74 (s, 3H), 3.31 (br, 1 H), 3.24-3.19 (m, 2H), 2.96-2.85 (m, 2H), 2.66-2.53 (m, 4H), 2.27-2.20 ( m, 2H), 2.16-2.05 (m, 2H), 1.96-1.80 (m, 2H), 1.75-1.63 (m, 4H), 1.63-1 48 (m, 2H).

Example 7 (1) (2R) -2- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid

TLC: Rf 0.20 (chloroform: methanol = 9: 1);

NMR (CDCl 3): δ 7.10-7.00 (m, 2H), 6.90-6.85 (m, 1H), 4.88-4.80 (m, 1H), 3.85 (s). ,

3H), 3.50 (br, q, J = 7.0 Hz, 1H), 3.28-3.04 (m, 3H), 3.00-2.90 (m, 1H), 2.50 -2.15 (m,

5H), 2.05-1.80 (m, 6H), 1.70-1.55 (m, 2H), 1.48 (br d, J = 7.0 Hz, 3H);

[α] _D = +10.69 (c 0.305, DMSO).

Example 7 (2) (2S) -2- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid

TLC: Rf 0.20 (chloroform: methanol = 9: 1);

NMR (CDCl 3): δ 7.10-7.00 (m, 2H), 6.90-6.80 (m, 1H), 4.86-4.58 (m, 1H), 3.84 (s). , 3H), 3.54-3.44 (m, 1H), 3.34-3.20 (m, 2H), 3.14-3.02 (m, 1H), 3.00-2.86 (m, 1H), 2.50-1.75 (m, 11H), 1.75-1.55 (m, 2H), 1.45 (brd, J = 7.0 Hz, 3H).

[α] _D = -10.40 (c 0.245, DMSO).

Example 8 to Example 8 (2)

The following compounds of the invention were obtained as described in Comparative Example 5 -> Example 3 using the compound prepared according to Examples 7 to 7 (2) instead of the compound prepared according to Example 2.

Example 8

N-Hydroxy-3- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanamide hydrochloride

TLC: Rf 0.52 (chloroform: methanol = 9: 1);

NMR (pyridine-ds + CDCl 3): δ 7.23 (d, J = 2.2 Hz, 1H), 7.11 (dd, J = 8.5, 2.2 Hz, 1H),

6.88 (d, J = 8.5 Hz, 1H), 6.53 (br, 3H), 4.86-4.79 (m, 1H), 3.72 (s, 3H), 3.37 -3.28 (m, 2H), 3.28 (t, J = 7.2 Hz, 2H), 2.93-2.83 (m, 2H), 2.85 (t, J = 7.2) Hz, 2H), 2.59-2.48 (m, 2H), 2.15-2.10 (m, 2H), 1.92-1.84 (m, 4H), 1.80-1, 65 (m, 2H); 1.54-1.41 (m, 2H).

Example 8 (1)

(2R) -N-Hydroxy-2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanamide hydrochloride

TLC: Rf 0.45 (chloroform: methanol = 9: 1);

NMR (pyridine-ds + CDCl 3): δ 7.08-7.00 (m, 1H), 7.00-6.95 (m, 1H), 6.85 (d, J = 8.7 Hz, 1H) ), 5.95-5.50 (m, 3H), 4.80-4.72 (m, 1H), 3.73 (s, 3H), 3.38-3.25 (m, 1H), 3.08-2.98 (m, 2H), 2.90-2.75 (m, 1H), 2.75-2.60 (m, 1H), 2.15-2.00 (m, 4H 1.95-1.65 (m, 6H), 1.55-1.45 (m, 2H), 1.43 (br d, J = 6.6 Hz, 3H), [α] _D = + 8.76 (c 0.37, DMSO).

Example 8 (2)

(2S) -N-Hydroxy-2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanamide hydrochloride

TLC: Rf 0.45 (chloroform: methanol = 9: 1);

NMR (pyridine-ds + CDCl 3): δ 7.11 (d, J = 2.1 Hz, 1H), 7.02 (dd, J = 2.1, 8.7 Hz, 1H),

6.88 (d, J = 8.7 Hz, 1H), 6.80-6.20 (m, 3H), 4.80-4.72 (m, 1H), 3.72 (s, 3H) , 3.40 (br, q, J = 6.9 Hz, 1H), 3.14-3.02 (m, 2H), 3.00-2.88 (m, 1H), 2.82-2 70 (m, 1H), 2.202.05 (m, 4H), 1.95-1.65 (m, 6H), 1.55-1.45 (m, 2H), 1.41 (d, J). = 6.9 Hz, 3H), [α] _D = -8.72 (c0.15, DMSO).

Comparative Example 6 1- (3-Cyclopentyloxy-4-methoxyphenyl) cyclopent-3-enecarbonitrile.

2- (3-Cyclopentyloxy-4-methoxyphenyl) ethanonitrile (4.0 g) was dissolved in tetrahydrofuran (75 mL) under argon. A 0.1 M tetrahydrofuran (40.4 mL) solution of hexamethyldisilazane was added dropwise at -78 ° C to the resulting solution. The resulting mixture was stirred at -78 ° C for 1 h, then diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1). The title compound (3.05 g) was obtained with the following physical properties

TLC: Rf 0.39 (hexane: ethyl acetate = 2: 1);

NMR (CDCl ₃ ): δ 7.00-6.95 (m, 2H), 6.82 (d, J = 8.7 Hz, 1H), 5.82 (s, 2H), 4.78 (m) (1H), 3.84 (s, 3H), 3.35-3.20 (m, 2H), 3.00-2.85 (m, 2H), 2.00-1.75 (m, 6H). ), 1.70-1.55 (m, 2H).

Comparative Example 7

2- (3-Cyclopentyloxy-4-methoxyphenyl) -4-oxo-2- (2-oxoethyl) butanenitrile

The compound of Comparative Example 6 (460 mg) was dissolved in methylene chloride (10 mL). An ozone stream is passed through the resulting solution at -78 ° C for 25 minutes. After addition of triphenylphosphine (513 mg), the reaction mixture was stirred at 78 ° C for 30 minutes, then at room temperature for 1 hour and concentrated in vacuo. This gave the title compound (1.27 g) which was used in the next reaction without further purification.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 9

2- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) -2-methylpropanoic acid benzyl ester

To a dichloroethane (10 mL) solution of the compound prepared according to Comparative Example 7 (1.27 g) and 2-amino-2-methylpropanoic acid benzyl ester (374 mg) was added sodium triacetoxy bromide (1.03 g) followed by acetic acid (0, 0 g). 56 ml). The reaction mixture was stirred at room temperature for 3 hours and then diluted with ethyl acetate. The ethyl acetate mixture was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1). There was thus obtained the compound of the invention (196 mg) with the following physical properties: TLC: Rf 0.62 (hexane: ethyl acetate = 2: 1);

NMR (CDCl 3): δ 7.45-7.30 (m, 5H), 7.05-6.95 (m, 2H), 6.85 (d, J = 9.0 Hz, 1H), δ, 19 (s, 2H), 4.80 (m, 1H), 3.84 (s, 3H), 3.05-2.95 (m, 2H), 2.80-2.60 (m, 2H) , 2.10-2.00 (m, 4H), 2.05-1.80 (m, 6H), 1.80-1.50 (m, 2H), 1.38 (s, 6H).

Example 10 to Example 10 (2)

The following compounds of the invention are obtained by the method described in Comparative Example 6 -> Comparative Example 7 -> Example 9 using 2- (3-cyclopentyloxy-4-methoxyphenyl) ethanonitrile or the corresponding nitrile derivative and 1-aminocyclopropanecarboxylic acid benzyl ester instead of benzyleste 2 amino-2 -methylpropanoic acid.

• «*«

Example 10

1- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid benzyl ester

TLC: Rf 0.50 (hexane: ethyl acetate = 2: 1);

NMR (CDCl 3): δ 7.50-7.30 (m, 5H), 7.00 (d, J = 2.1 Hz, 1H), 6.98 (dd, J = 9.0, 2.1) Hz, 1H), 6.84 (d, J = 9.0 Hz, 1H), 5.19 (s, 2H), 4.80 (m, 1H), 3.84 (s, 3H), 3, 65-3.50 (m, 2H), 3.00-2.90 (m, 2H), 2.10-2.00 (m, 2H), 2.00-1.75 (m, 8H), 1.70-1.55 (m, 2H), 1.40-1.35 (m, 2H), 1.00-0.95 (m, 2H).

Example 10 (1)

1- (4- (3-Ethoxy-4-methoxyphenyl-4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid benzyl ester

TLC: Rf 0.48 (ethyl acetate: hexane = 1: 3);

NMR (CDCl 3): δ 7.45-7.28 (m, 5H), 7.02-6.97 (m, 2H), 6.85 (d, J = 9.0 Hz, 1H), δ, 20 (s, 2H), 4.12 (q, J = 7.0 Hz, 2H), 3.87 (s, 3H), 3.62-3.51 (m, 2H), 3.00-2 , 91 (m, 2H), 2.08-2.00 (m, 2H), 1.90-1.79 (m, 2H), 1.47 (t, J = 7.0 Hz, 3H), 1.38-1.34 (m, 2H); 0.99-0.94 (m, 2H).

• 0 • 4 • «• · · 0 <· *

0 0

Example 10 (2)

1- (4- (3-Methoxymethoxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid benzyl ester

TLC: Rf 0.45 (ethyl acetate: hexane = 1: 2);

NMR (CDCl 3): δ 7.45-7.29 (m, 5H), 7.22 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 8.4 Hz, 2, 4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.23 (s, 2H), 5.19 (s, 2H), 3.88 (s, 3H), 3 61-3.50 (m, 2H); 3.53 (s, 3H); 3.00-2.92 (m, 2H); 2.08-2.00 (m, 2H); -1.78 (m, 2H), 1.381.34 (m, 2H), 1.00-0.95 (m, 2H).

Example 11

1- (4- (3-Hydroxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid benzyl ester hydrochloride

To a methylene chloride (10 mL) solution of the compound prepared according to Example 10 (2) was added a 4M solution of hydrogen chloride in ethyl acetate (10 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was washed with ethyl acetate. The compound of the invention (1.51 g) was obtained with the following properties.

TLC: Rf 0.38 (ethyl acetate: hexane = 1: 2);

NMR (CDCl 3): δ 7.42-7.32 (m, 5H), 7.19 (d, J = 2.7 Hz, 1H), 7.07 (dd, J = 8.4 Hz, 2, 7 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.90-5.83 (bs, 1H), 5.22 (s, 2H), 4.50-4, 36 (m, 2 H),

3.89 (s, 3H), 3.56-3.47 (m, 2H), 3.27-3.09 (m, 2H), 2.30-2.23 (m, 2H), 2, 22-2.12 (m, 2H), 1.72-1.65 (m, 2H), 1.70-1.50 (br, 1H).

Example 12

1- (4- (3-Cyclopropylmethoxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid benzyl ester

To a dimethylformamide (5 mL) solution of the compound prepared according to Example 11 (664 mg) was added cyclopropylmethyl bromide (0.22 mL) followed by sodium carbonate (518 mg). The resulting mixture was stirred at room temperature overnight, then poured into ice water and extracted with ethyl acetate. The extract was washed with 1M hydrochloric acid, then with saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1). The compound of the invention (763 mg) was obtained with the following physical properties

TLC: Rf 0.57 (ethyl acetate: hexane = 1: 2);

NMR (CDCl 3): δ 7.45-7.28 (m, 5H), 7.02-6.96 (m, 2H), 6.87-6.82 (m, 1H), 5.19 (s). , 2H), 3.88-3.84 (m, 5H), 3.61-3.49 (m, 2H), 3.00-2.90 (m, 2H), 2.08-1.99 (m, 2H), 1.90-1.77 (m, 2H), 1.38-1.32 (m, 2H), 0.98-0.96 (m, 2H), 0.69-0 , 61 (m, 2H), 0.40-0.33 (m, 3H).

Example 13

1- (4- (3-Cyclobutyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid benzyl ester

To a tetrahydrofuran (5 mL) suspension of the compound prepared as described above, triethylamine (0.21 mL), cyclobutanol (0.18 mL), triphenylphosphine (878 mg) and diethyldicarboxylate (0.47 mL) were added at room temperature. The resulting mixture was stirred at room temperature overnight and then purified by silica gel column chromatography.

(hexane: ethyl acetate = 7: 2). There was obtained the compound of the invention (683 mg) with the following physical properties: TLC: Rf 0.52 (ethyl acetate: hexane = 1: 2);

NMR (CDCl 3): δ 7.45-7.29 (m, 5H), 6.97 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.87 (d, J = 2, 4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.19 (s, 2H), 4.69 (quint, J = 7.0 Hz, 1H), 3.86 (s, 3H), 3.61-3.50 (m, 2H), 3.00-2.90 (m, 2H), 2.55-2.43 (m, 2H), 2.33-2 18 (m, 2H), 2.08-1.99 (m, 2H), 1.89-1.60 (m, 4H), 1.38-1.34 (m, 2H), 0.99 -0.94 (m, 2H).

Example 14

2- (4- (3-Cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) -2-methylpropanoic acid

Example 9 (180 mg) was dissolved in methanol (4 mL) and tetrahydrofuran (4 mL). To this solution was added 10% palladium on carbon (20 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1.5 hours, then filtered through celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol: water = 10: 2: 0.1). The compound of the invention (140 mg) was obtained with the following physical properties

TLC: Rf 0.34 (chloroform: methanol = 10: 1);

NMR (DMSO-d 6): δ 7.05-6.90 (m, 3H), 4.84 (m, 1H), 3.74 (s, 3H), 3.80-3.00 (br, 1H) ), 3.15-3.00 (m, 2H), 2.65-2.50 (m, 2H), 2.20-2.05 (m, 2H), 2.10-1.95 (m (2H), 2.00-1.80 (m, 2H), 1.80-1.60 (m, 4H), 1.65-1.55 (m, 2H), 1.25 (s, 6H ).

Example 14 (1) to Example 14 (4)

The following compounds of the invention were prepared in the same manner as described in Example 14 using the compound prepared according to Example 10, 10 (1), 12 or 13 instead of the compound prepared according to Example 9.

Example 14 (1)

· 1- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid · · · · · · · · ·

TLC: Rf 0.45 (chloroform: methanol = 10: 1);

NMR (DMSO-d 6): δ 12.29 (br s, 1H), 7.05-6.90 (m, 3H), 4.82 (m, 1H), 3.73 (s, 3H), 3 , 45-3.30 (m, 2H), 2.95-2.85 (m, 2H), 2.10-1.95 (m, 2H), 2.00-1.60 (m, 8H) , 1.65-1.50 (m, 2H), 1.25-1.10 (m, 2H), 0.95-0.80 (m, 2H).

Example 14 (2)

1- (4- (3-Ethoxy-4-methoxyphenyl-4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid

TLC: Rf 0.38 (dichloromethane: methanol = 9: 1);

NMR (DMSO-d 6): δ 12.45-12.15 (br, 1H), 7.03-6.93 (m, 3H), 4.04 (q, J = 6.9 Hz, 2H), 3.75 (s, 3H), 3.45-3.35 (m, 2H), 2.95-2.86 (m, 2H), 2.09-1.98 (m, 2H), 1, 86-1.72 (m, 2H), 1.32 (t, J = 6.9 Hz, 3H), 1.21-1.16 (m, 2H), 0.92-0.86 (m, 2H).

Example 14 (3)

1- (4- (3-Cyclopropylmethoxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid

TLC: Rf 0.35 (ethyl acetate: hexane = 1: 1);

·· ·· ·· ··· ····

NMR (DMSO-d 6): δ 12.5-12.0 (br, 1H), 7.04-6.93 (m, 3H), 3.82 (d, J = 7.2 Hz, 2H), 3.77 (s, 3H), 3.46-3.36 (m, 2H), 2.94-2.86 (m, 2H), 2.07-1.97 (m, 2H), 1, 85-1.71 (m, 2H), 1.26-1.14 (m, 3H), 0.91-0.85 (m, 2H), 0.60-0.53 (m, 2H), 0.35-0.28 (m, 2H).

Example 14 (4)

1- (4- (3-Cyclobutyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid

TLC: Rf 0.36 (dichloromethane: methanol = 19: 1);

NMR (DMSO-d 6): δ 12.5-12.1 (br, 1H), 7.01-6.93 (m, 2H), 6.84 (d, J = 1.8 Hz, 1H), 4.73 (quint, J = 7.5 Hz, 1H), 3.75 (s, 3H), 3.44-3.36 (m, 2H), 2.95-2.86 (m, 2H) , 2.463.33 (m, 2H), 2.11-1.96 (m, 4H), 1.83-1.55 (m, 4H), 1.21-1.15 (m, 2H), O , 92-0.86 (m, 2H).

Example 15 to Example 15 (4)

The following compounds of the invention were prepared in the same manner as in Comparative Example 5-Example 3 using the compound prepared according to Example 14 to Example 14 (4) instead of the compound prepared according to Example 2.

Example 15

N-Hydroxy-2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyano-piperidin-1-yl) -2-methylpropanamide hydrochloride

TLC: Rf 0.38 (chloroform: methanol = 10: 1);

NMR (pyridine-ds + CDCl 3): δ 7.14 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 8.4, 2.1 Hz, 1H),

6.91 (d, J = 8.4 Hz, 1H), 5.95 (br s, 3H), 4.72 (m, 1H), 3.73 (s, 3H), 3.10-3, 00 (m,

2Η), 2.80-2.65 (m, 2Η), 2.20-2.00 (m, 4H), 2.00-1.70 (m, 6H), 1.60-1.40 ( m, 2H), 1.39 (s, 6H).

Example 15 (1)

N-Hydroxy-1- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyano-piperidin-1-yl) cyclopropanecarboxamide hydrochloride

TLC: Rf 0.45 (chloroform: methanol = 10: 1);

NMR (pyridine-ds + CDCl 3): δ 7.12 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.4, 2.4 Hz, 1H), 6.87 ( d, J = 8.4 Hz, 1H), 6.90-6.00 (br, 3H), 4.75 (m, 1H), 3.73 (s, 3H), 3.00-2.90 (m, 2H), 2.90-2.70 (m, 2H), 2.20-2.00 (m, 4H), 2.00-1.60 (m, 6H), 1.60-1 , 40 (m, 2H), 1.35-1.25 (m, 2H), 1.10-1.00 (m, 2H).

Example 15 (2)

N-Hydroxy-1- (4- (3-ethoxy-4-methoxyphenyl-4-cyanopiperidin-1-yl) cyclopropanecarboxamide hydrochloride

TLC: Rf 0.42 (dichloromethane: methanol = 9: 1);

NMR (pyridine-ds + CDCl 3): δ 8.00-7.20 (br, 3H), 7.09 (d, J = 1.8 Hz, 1H), 7.04 (dd, J = 8.4) , 1.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 3.91 (q, J = 6.9 Hz, 2H), 3.74 (s, 3H), 2.992.79 (m, 4H), 2.19-2.10 (m, 4H), 1.37-1.27 (m, 5H), 1.09-1.03 (m, 2H).

• · · ·

Example 15 (3)

N-Hydroxy-1- (4- (3-cyclopropylmethoxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclopropanecarboxamide hydrochloride

TLC: Rf 0.60 (dichloromethane: methanol = 9: 1);

NMR (pyridine-ds + CDCl 3): δ 8.60-6.80 (br, 3H), 7.15 (d, J = 2.0 Hz, 1H), 7.05 (dd, J = 9.0) , 2.0 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 3.81 (d, J = 6.9 Hz, 2H), 3.73 (s, 3H), 2.992.79 (m, 4H), 2.20-2.02 (m, 4H), 1.37-1.31 (m, 2H), 1.31-1.20 (m, 1H), 1, 08-1.03 (m, 2H), 0.55-0.47 (m, 2H), 0.32-0.26 (m, 2H).

Example 15 (4)

N-Hydroxy-1- (4- (3-cyclobutyloxy-4-methoxyphenyl) -4-cyano-piperidin-1-yl) cyclopropanecarboxamide hydrochloride

TLC: Rf 0.64 (dichloromethane: methanol = 9: 1);

NMR (pyridine-ds + CDCl 3): δ 8.00-7.10 (br, 3H), 7.04 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.4) , 2.1 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.62 (quint, J = 7.5 Hz, 1H), 3.75 (s, 3H), 3.00-2.80 (m, 4H), 2.42-2.30 (m, 2H), 2.23-2.02 (m, 6H), 1.74-1.60 (m, 1H ), 1.58-1.40 (m, 1H), 1.38-1.32 (m, 2H), 1.09-1.03 (m, 2H).

Example 16 to Example 16 (1)

The following compounds of the invention were prepared in the same manner as described in Comparative Example 6 - Comparative Example 7-> Example 9 using the corresponding nitrile derivative instead of 2- (3-cyclopentyloxy-4-methoxyphenyl) ethanonitrile and using the corresponding derivative instead of benzyl 2- amino-2-methylpropanoic acid.

• · · ·

....

Example 16

2- (4- (3-Benzyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester

TLC: Rf 0.31 (hexane: ethyl acetate = 2: 1);

NMR (CDCl 3): δ 7.50-7.40 (m, 2H), 7.45-7.25 (m, 3H), 7.10-7.00 (m, 2H), 6.89 (d) , J = 8.7 Hz, 1H), 5.15 (s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.30 (s). (2H), 3.153.00 (m, 2H), 2.70-2.55 (m, 2H), 2.20-2.05 (m, 2H), 2.15-1.95 (m, 2H ), 1.30 (t, J = 7.2 Hz, 3H).

Example 16 (1)

2- (4- (3-Benzyloxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid methyl ester

TLC: Rf 0.31 (hexane: ethyl acetate = 1: 1);

NMR (CDCl 3): δ 7.42-7.30 (m, 5H), 7.20 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H) , 7.07 (dd, J = 8.1, 2.4 Hz, 1H), 6.58 (t, J = 75.0 Hz, 1H), 5.15 (s, 2H), 3.76 ( s, 3H), 3.32 (s, 2H), 3.08 (dt, J = 12.0, 2.7 Hz, 2H), 2.66 (td, J = 12.0, 2.7 Hz) (2H), 2.18 (td, J = 12.0, 3.9 Hz, 2H), 2.09-2.01 (m, 2H).

Example 17 to Example 17 (1)

The following compounds of the invention were prepared in the same manner as described in Example 14 using the compound prepared according to Example 16 or Example 16 (1) instead of the compound prepared according to Example 9.

Example 17

2- (4- (3-Hydroxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester • · · · ·

XH

O

TLC: Rf 0.43 (hexane: ethyl acetate = 1: 2);

NMR (CDCl 3): δ 7.06 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 8.1, 2.4 Hz, 1H), 6.85 (d, J =

8.1 Hz, 1H), 5.66 (br, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.30 (s, 2H) , 3.113.03 (m, 2H), 2.72-2.62 (m, 2H), 2.20-2.04 (m, 4H), 1.30 (t, J = 7.2 Hz, 3H ).

Example 17 (1)

2- (4- (3-Hydroxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid methyl ester

TLC: Rf 0.55 (chloroform: methanol = 9: 1);

NMR (CDCl 3): δ 7.16 (d, J = 2.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.02 (dd, J = 8.4,

2.4 Hz, 1H), 6.54 (t, J = 73.5 Hz, 1H), 3.76 (s, 3H), 3.32 (s, 2H), 3.07 (d, J = 12.0 Hz, 2H), 2.66 (td, J = 12.0, 2.7 Hz, 2H), 2.16 (td, J = 13.5, 3.9 Hz, 2H), 2, 12-2.03 (m, 3H).

Example 18 to Example 18 (2)

The following compounds of the invention were prepared in the same manner as described in Example 13 using the compound prepared according to Example 17 or Example 17 (1) instead of the compound prepared according to Example 11 using cyclobutyl alcohol or the corresponding alcohol.

Example 18

2- (4- (3- (Indan-2-yloxy) -4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester

TLC: Rf 0.62 (hexane: ethyl acetate = 1: 2);

NMR (CDCl 3): δ 7.26-7.16 (m, 4H), 7.09-7.05 (m, 2H), 6.90-6.86 (m, 1H), 5.20 (m). (1H), 4.22 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 3.44-3.35 (m, 2H), 3.31 (s, 2H) , 3.27-3.19 (m, 2H), 3.14-3.05 (m, 2H), 2.73-2.63 (m, 2H), 2.26-2.16 (m, 2H), 2.15-2.06 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H).

Example 18 (1)

2- (4- (3-Cyclobutyloxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid methyl ester

TLC: Rf 0.54 (ethyl acetate: toluene = 1: 1);

NMR (CDCl 3): δ 7.17 (d, J = 8.1 Hz, 1H), 7.02 (dd, J = 8.1, 2.1 Hz, 1H), 6.97 (d, J =

2.1 Hz, 1H), 6.58 (t, J = 75.0 Hz, 1H), 4.69 (m, 1H), 3.76 (s, 3H), 3.33 (s, 2H) , 3.09 (dt, J = 12.3, 2.7 Hz, 2H), 2.66 (td, J = 12.3, 2.7 Hz, 2H), 2.54-2.43 (m (2H), 2.29, 2.13 (m, 4H), 2.11-2.02 (m, 2H), 1.89 (m, 1H), 1.72 (m, 1H).

Example 18 (2)

2- (4- (3- (Indan-2-yloxy) -4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid methyl ester

TLC: Rf 0.29 (hexane: ethyl acetate = 1: 1);

NMR (CDCl 3): δ 7.27-7.16 (m, 6H), 7.07 (dd, J = 8.1, 2.4 Hz, 1H), 6.38 (t, J = 75.3 Hz, 1H), 5.26-5.20 (m, 1H), 3.76 (s, 3H), 3.41 (dd, J = 16.5, 6.3 Hz, 2H), 3.34 (s, 2H), 3.20 (dd, J = 16.5, 3.3 Hz, 2H), 3.11 (d, J = 12.0 Hz, 2H), 2.69 (dt, J = 12.0, 2.4 Hz, 2H), 2.28-2.19 (m, 2H), 2.14-2.04 (m, 2H).

Example 19 to Example 19 (5)

The following compounds of the invention were prepared in the same manner as described in Example 12 using the compound prepared according to Example 17 (1) instead of the compound prepared according to Example 11 using cyclopropylmethyl bromide or the corresponding halogen derivative.

Example 19

2- (4- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -4-cyano-piperidin-1-yl) -acetic acid methyl ester

O

TLC: Rf 0.80 (chloroform: methanol = 9: 1);

NMR (CDCl 3): δ 7.18 (d, J = 8.1 Hz, 1H), 7.09-7.03 (m, 2H), 6.63 (t, J = 75.6 Hz, 1H) , 3.88 (d, J = 6.9 Hz, 2H), 3.76 (s, 3H), 3.32 (s, 2H), 3.08 (dt, J = 12.0, 2.7) Hz, 2H), 2.66 (td, J = 12.0, 2.7 Hz, 2H), 2.27-2.15 (m, 2H), 2.12-2.05 (m, 2H) 1.28 (m, 1H); 0.69-0.63 (m, 2H);

Example 19 (1)

2- (4- (3-Cyclobutylmethoxy-4-difluoromethoxyphenyl) -4-cyano-piperidin-1-yl) -acetic acid methyl ester • · · ·

TLC: Rf 0.84 (chloroform: methanol = 9: 1);

NMR (CDCl 3): δ 7.17 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 2.1 Hz, 1H), 7.05 (dd, J = 8.4,

2.1 Hz, 1H), 6.57 (t, J = 75.3 Hz, 1H), 3.99 (d, J = 6.6 Hz, 2H), 3.76 (s, 3H), 3 , 33 (s, 2H), 3.09 (dt, J = 11.7, 2.4 Hz, 2H), 2.81 (m, 1H), 2.67 (td, J = 11.7, 2) 4 Hz, 2H), 2.28-1.82 (m, 10H).

Example 19 (2)

Methyl 2- (4- (3-ethoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.33 (hexane: ethyl acetate = 1: 2);

NMR (CDCl 3): δ 7.17 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 2.1 Hz, 1H), 7.04 (dd, J = 8.4,

2.1 Hz, 1H), 6.57 (t, J = 75.3 Hz, 1H), 4.11 (q, J = 6.9 Hz, 2H), 3.75 (s, 3H), 3 , 32 (s, 2H), 3.08 (d, J = 12.0 Hz, 2H), 2.66 (dt, J = 12.0, 2.7 Hz, 2H), 2.26-2, 16 (m, 2H), 2.10-2.05 (m, 2H), 1.46 (t, J = 6.9 Hz, 3H).

Example 19 (3)

2- (4- (3-Butoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid methyl ester

'CH,

TLC: Rf 0.57 (hexane: ethyl acetate = 1: 1);

NMR (CDCl 3): δ 7.17 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 7.05 (dd, J = 8.5,

2.2 Hz, 1H), 6.56 (t, J = 75.0 Hz, 1H), 4.03 (t, J = 6.5 Hz, 2H), 3.76 (s, 3H), 3 , 33 (s,

2H), 3.13-3.05 (m, 2H), 2.72-2.62 (m, 2H), 2.27-2.17 (m, 2H), 2.11-2.04 ( m, 2H),

1.86-1.76 (m, 2H), 1.60-1.45 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

Example 19 (4)

2- (4- (3-Propoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid methyl ester

TLC: Rf 0.56 (hexane: ethyl acetate = 1: 1);

NMR (CDCl 3): δ 7.18 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.05 (dd, J = 8.1,

2.4 Hz, 1H), 6.57 (t, J = 75.0 Hz, 1H), 3.99 (t, J = 7.0 Hz, 2H), 3.76 (s, 3H), 3 33 (s, 2H), 3.15-3.00 (m, 2H), 2.75-2.60 (m, 2H), 2.30-2.15 (m, 2H), 2.15. -2.00 (m, 2H), 1.86 (sext, J = 7.0 Hz, 2H), 1.06 (t, J = 7.0 Hz, 3H).

Example 19 (5)

2- (4- (3- (2-Methylpropoxy) -4-difluoromethoxyphenyl) -4-cyano-piperidin-1-yl) acetic acid methyl ester

TLC: Rf 0.40 (hexane: ethyl acetate = 1: 1);

NMR (CDCl 3): δ 7.18 (d, J = 7.8 Hz, 1H), 7.10-7.00 (m, 2H), 6.56 (t, J = 75.3 Hz, 1H) , 3.78 (d, J = 6.6 Hz, 2H), 3.76 (s, 3H), 3.33 (s, 2H), 3.20-3.00 (m, 2H), 2, 80-2.60 (m, 2H), 2.30-2.15 (m, 2H), 2.25-2.00 (m, 1H), 2.20-2.00 (m, 2H), 1.05 (d, J = 6.6 Hz, 6H).

Example 20 to Example 20 (8)

The following compounds of the invention were prepared in the same manner as in Example 2 using the compound prepared according to Example 18 to the Example

18 (2) or Example 19 to Example 19 (5) instead of the compound prepared according to Example 1.

The compound prepared according to Example 20 (3) is also converted into the hydrochloride in a known manner.

Example 20

2- (4- (3- (Indan-2-yloxy) -4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.68 (chloroform: methanol: acetic acid = 30: 2: 1);

NMR (DMSO-d 6): δ 7.28-7.23 (m, 2H), 7.19-7.13 (m, 2H), 7.10 (d, J = 1.8 Hz, 1H), 7.06 (dd, J = 8.6, 1.8 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 5.28 (m, 1H), 3.69 (s). , 3H), 3.80-2.60 (br, 1H), 3.39-3.30 (m, 2H), 3.25 (s, 2H), 3.16-2.98 (m, 4H ), 2.66-2.53 (m, 2H), 2.15-1.97 (m, 4H).

Example 20 (1)

2- (4- (3-Cyclobutyloxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.67 (chloroform: methanol = 3: 1);

NMR (DMSO-d 6) δ 7.21 (d, J = 8.1 Hz, 1H), 7.10 (dd, J = 8.1, 2.1 Hz, 1H), 7.08 (t, J = 74.4 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 4.85 (m, 1H), 4.25-2.60 (br s, 1H), 3 , 24 (s, 2H), 3.01 (br d, J = 12.0 Hz, 2H), 2.58 (br t, J = 12.0 Hz, 2H), 2.48-2.34 ( m, 2H), 2.16-1.94 (m, 6H), 1.77 (m, 1H), 1.62 (m, 1H).

Example 20 (2)

2- (4- (3- (Indan-2-yloxy) -4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid;

TLC: Rf 0.24 (chloroform: methanol: acetic acid = 9: 1: 0.1);

NMR (DMSO-d 6): δ 7.32-7.14 (m, 7H), 6.91 (t, J = 74.4 Hz, 1H), 5.43-5.37 (m, 1H), 4.00-2.60 (br, 1H), 3.39 (dd, J = 16.8, 6.0 Hz, 2H), 3.24 (s, 2H), 3.07-3.00 ( m, 4H), 2.60 (dt, J = 11.7, 3.0 Hz, 2H), 2.17-2.03 (m, 4H).

Example 20 (3)

2- (4- (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl) -4-cyano-piperidin-1-yl) -acetic acid hydrochloride

TLC: Rf 0.61 (chloroform: methanol = 2: 1);

NMR (DMSO-d 6): δ 7.21-7.14 (m, 2H), 7.02 (t, J = 74.4 Hz, 1H), 7.01 (dd, J = 8.7, 2) 1 Hz, 1H), 4.12 (s, 2H), 3.95-2.95 (br s, 2H), 3.85 (d, J = 6.9 Hz, 2H), 3.58 ( br d, J = 12.0 Hz, 2H), 3.23 (br t, J = 12.0 Hz, 2H), 2.54-2.31 (m, 4H), 1.14 (m, 1H) ), 0.47 (m, 2H), 0.24 (m, 2H).

Example 20 (4)

2- (4- (3-Cyclobutylmethoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

NC

AND-

OH «

TLC: Rf 0.53 (chloroform: methanol = 3: 1);

NMR (DMSO-d 6): δ 7.25 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 8, 4, 2.4 Hz, 1H), 7.03 (t, J = 74.4 Hz, 1H), 4.06 (d, J = 6.6 Hz, 2H), 4.00-2.80 ( br s, 1 H), 3.24 (s, 2H), 3.02 (br d, J = 12.0 Hz, 2H), 2.72 (m, 1H), 2.59 (td, J = 12) 2.17-1.95 (m, 6H); 2.00-1.75 (m, 4H).

Example 20 (5)

2- (4- (3-Ethoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.15 (chloroform: methanol: acetic acid = 9: 1: 0.1);

NMR (DMSO-d 6): δ 7.22-7.19 (m, 2H), 7.09 (dd, J = 8.4, 2.1 Hz, 1H), 7.06 (t, J =

74.4 Hz, 1H), 4.13 (q, J = 6.9 Hz, 2H), 4.00-3.00 (br, 1H), 3.21 (s, 2H), 3.01 ( d, J = 12.0 Hz, 2H), 2.57 (dt, J = 11.7, 3.0 Hz, 2H), 2.13-1.99 (m, 4H), 1.32 (t J = 6.9 Hz, 3H).

Example 20 (6)

2- (4- (3-Butoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.56 (chloroform: methanol: acetic acid = 10: 2: 1);

NMR (CDCl ₃ + DMSO-d 6): δ 7.17 (d, J = 8.1 Hz, 1H), 7.09 (dd, J = 8.1, 2.1 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.57 (t, J = 75.2 Hz, 1H), 4.03 (t, J = 6.5 Hz, 2H), 3.57 (br (1H), 3.29 (s, 2H), 3.20-3.10 (m, 2H), 2.72-2.61 (m, 2H), 2.30-2.19 (m, 2H) ), 2.13-2.05 (m, 2H), 1.86-1.76 (m, 2H), 1.58-1.44 (m, 2H), 0.99 (t, J = 7 5 Hz, 3H).

Example 20 (7)

2- (4- (3-Propoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.60 (chloroform: methanol: acetic acid = 10: 2: 1);

NMR (DMSO-d 6): δ 12.40-11.00 (br, 1H), 7.30-7.15 (m, 2H), 7.11 (dd, J = 8.7, 2.7)

Hz, 1H), 7.05 (t, J = 74.4 Hz, 1H), 4.04 (t, J = 6.6 Hz, 2H), 3.23 (s, 2H), 3.10- 2.95 (m,

2H), 2.70-2.50 (m, 2H), 2.20-2.00 (m, 4H), 1.74 (sext, J = 6.6 Hz, 2H), 0.98 (t , J = 6.6

Hz, 3H).

Example 20 (8)

2- (4- (3- (2-Methylpropoxy) -4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid

TLC: Rf 0.63 (chloroform: methanol: acetic acid = 10: 2: 1);

NMR (DMSO-d 6): δ 12.20-10.80 (br, 1H), 7.25-7.20 (m, 2H), 7.11 (dd, J = 8.7, 2.4 Hz) (1H), 7.04 (t, J = 74.4 Hz, 1H), 3.86 (d, J = 6.3 Hz, 2H), 3.23 (s, 2H), 3.10-2 95 (m, 2H), 2.65-2.50 (m, 2H), 2.20-2.00 (m, 5H), 0.98 (d, J = 6.6 Hz, 6H).

Comparative Example 8

3- (3-Cyclopentyloxy-4-methoxyphenyl) -2,4-bis (ethoxycarbonyl) -5-hydroxy-5-methylcyclohexan-1-one

CH ₃

3-Cyclopentyloxy-4-methoxybenzaldehyde (30 g) and ethyl acetoacetate (33.36 ml) were dissolved in ethanol (7 ml). To this solution was added piperidine (4 mL). The reaction mixture was stirred at room temperature overnight and ethanol was added. The solid was filtered and the filtrate was washed with ethanol. The title compound (37.1 g) was obtained with the following physical properties

TLC: Rf 0.55 (hexane: ethyl acetate = 1: 1);

NMR (DMSO-d 6): δ 6.87 (d, J = 1.8 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 8, 4.83 Hz, 1H), 4.83 (s, 1H), 4.75-4.69 (m, 1H), 3.95-3.70 (m, 6H), 3.67 (s). , 3H), 3.26 (d, J = 12.0 Hz, 1H), 2.90 (d, J = 13.5 Hz, 1H), 2.31 (d, J = 13.5 Hz, 1H) ), 1.901.78 (m, 2H), 1.78-1.63 (m, 4H), 1.63-1.53 (m, 2H), 1.23 (s, 3H), 0.96 ( t, J = 7.2 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H).

Comparative Example 9

3- (3-Cyclopentyloxy-4-methoxyphenyl) -3-carboxymethylpropanoic acid

The compound of Comparative Example 8 (37.1 g) was dissolved in ethanol (370 mL) and tetrahydrofuran (200 mL). Sodium hydroxide (200 g) and water (200 ml) were added to the solution. The reaction mixture was refluxed for 5 hours, then cooled to room temperature and the ethanol evaporated under reduced pressure. The residue was neutralized with concentrated hydrochloric acid (410 mL) under ice-cooling and extracted with ethyl acetate. The extract was washed with water and then with saturated brine and concentrated in vacuo. The title compound (26.28 g) was obtained with the following physical properties. The resulting product was used in the subsequent reaction without purification.

TLC: Rf 0.58 (chloroform: methanol = 5: 1);

NMR (DMSO-d 6): δ 12.01 (br, 2H), 6.83-6.79 (m, 2H), 6.72 (dd, J = 8.3, 2.0 Hz, 1H), 4.77-4.71 (m, 1H), 3.68 (s, 3H), 3.38-3.30 (m, 1H), 2.59 (dd, J = 15.6, 6.3) Hz, 2H), 2.46 (dd, J = 15.6, 8.4 Hz, 2H), 1.92-1.78 (m, 2H), 1.76-1.62 (m, 4H) , 1.62-1.46 (m, 2H).

Comparative Example 10

4- (3-Cyclopentyloxy-4-methoxyphenyl) piperidine-2,6-dione.

To the compound prepared according to Comparative Example 9 (26.28 g) was added urea (14.5 g). The resulting mixture was stirred at 165 ° C for 4 hours, then cooled to room temperature and dichloromethane was added. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue. The residue is triturated and then crystallized. The resulting crystals are filtered off and dried. There was thus obtained the title compound (14.02 g) having the following physical properties: TLC: Rf 0.77 (chloroform: methanol = 5: 1);

NMR (DMSO-d 6): δ 10.79 (s, 1H), 6.89-6.85 (m, 2H), 6.75 (dd, J = 8.4, 2.1 Hz, 1H), 4.76 (m, 1H), 3.70 (s, 3H), 3.35 (m, 1H), 2.77 (dd, J = 16.8, 10.8 Hz, 2H), 2.61 (dd, J = 16.8, 4.7 Hz, 2H), 1.95-1.80 (m, 2H), 1.78-1.61 (m, 4H), 1.61-1.50 (m, 2H).

Comparative Example 11 4- (3-Cyclopentyloxy-4-methoxyphenyl) piperidine hydrochloride

Lithium aluminum hydride (7.0 g) was suspended in tetrahydrofuran (150 mL). To the resulting suspension, a solution of the compound prepared according to Comparative Example 10 was added at an internal temperature of 30 ° C or less, under ice-cooling. saturated aqueous sodium sulfate solution (30 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour and ether (200 mL) and anhydrous magnesium sulfate were added. The reaction mixture was stirred at room temperature for 2 hours and then filtered through celite. The filtrate was concentrated under reduced pressure. A 4M solution of hydrogen chloride in ethyl acetate (6 mL) was added to the residue. The resulting mixture was stirred and then concentrated under reduced pressure. The title compound (7.2 g) is obtained with the following physical properties

TLC: Rf 0.15 (chloroform: methanol = 9: 1);

NMR (DMSO-d ₆ ): δ 6.83 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 1.9 Hz, 1H), 6.68 (dd, J = 8 1.75 Hz, 1H), 4.75 (m, 1H), 3.68 (s, 3H), 3.36 (m, 1H), 3.31 (br, 2H), 3.02 -2.94 (m, 2H), 2.58-2.52 (m, 2H), 1.94-1.39 (m, 12H).

Example 21

2- (4- (3-Cyclopentyloxy-4-methoxyphenyl) piperidin-1-yl) acetic acid ethyl ester

Using the method of Example 1, using the compound of Comparative Example 11, instead of the compound of Comparative Example 4, a compound of the invention having the following physical properties was prepared.

TLC: Rf 0.61 (hexane: ethyl acetate = 1: 1);

NMR (CDCl ₃ ): δ 6.82-6.71 (m, 3H), 4.75 (m, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.82 (s) 3.25 (s, 2H); 3.10-3.02 (m, 2H); 2.43 (m, 1H); 2.33-2.23 (m, 2H); 95-1.75 (m, 10H), 1.70-1.50 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H).

Example 22

2- (4- (3-Cyclopentyloxy-4-methoxyphenyl) piperidin-1-yl) acetic acid

Using the method of Example 2, using the compound of Example 21, instead of the compound of Example 1, a compound of the invention having the following physical properties was prepared.

TLC: Rf 0.44 (chloroform: methanol = 5: 1);

NMR (DMSO-d ₆ ): δ 6.88 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 1.8 Hz, 1H), 6.73 (dd, J = 8 1.81 Hz, 1H), 4.79-4.72 (m, 1H), 4.11 (s, 2H), 3.70 (s, 3H), 3.59-3.49 ( m, 2H), 3.32 (br, 1H), 3.18-3.05 (m, 2H), 2.74-2.68 (m, 1H), 2.04-1.80 (m, 6H), 1.77-1.63 (m, 4H), 1.63-1.50 (m, 2H).

Formulation Example 1

The following ingredients are mixed in the usual manner. The resulting tablet is compressed into 100 tablets, each containing 50 mg of active ingredient.

N-hydroxy-2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetamide hydrochloride 5.0 g Carboxymethylcellulose calcium salt (disintegrant) 0.2 g magnesium stearate 0, 1 g microcrystalline cellulose 4.7 g

Formulation Example 2

The following ingredients are mixed in the usual manner. The resulting solution is sterilized in the usual manner, filled in 5 ml ampoules and lyophilized. 100 ampoules are obtained, each containing 20 mg of active ingredient.

N-hydroxy-2- (4-3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetamide hydrochloride ..... 2.0 g mannitol .... 20 g distilled water. .1000 ml

Claims

PATENT CLAIMS

Piperidine derivatives of the general formula I wherein:

R ¹

R ² and R ³ represent 1) a hydrogen atom or 2) a cyano group:

each is independently 1) C 1-8 alkyl, 2) C 3-7 cycloalkyl, 3) C 1-8 alkyl substituted with C 3-7 cycloalkyl, 4) C 1-8 alkyl substituted with 1 to 3 halogen atoms, 5) hydrogen, 6) C1 -8 alkyl substituted by phenyl, 7) C1-8 alkyl substituted by C1-8 alkoxy, or 8) a group of the formula wherein n is 1 to 5;

R ⁴ and R ⁵

R ⁶ m

each independently is 1) a hydrogen atom or 2) a C 1-8 alkyl group, or taken together with the carbon atom to which they are attached to form a C 3-7 saturated carbocyclic ring;

is 1) hydroxy, 2) C 1-8 alkoxy, 3) -NHOH or 4) C 1-8 alkoxy substituted by phenyl; a is 0 or an integer of 1 to 4;

and non-toxic salts thereof.

Piperidine derivatives according to claim 1

Wherein R ⁶ 'is 1) a hydroxy group, 2) a C 1-8 alkoxy group, or 4) a C 1-8 alkoxy group substituted with a phenyl group; and the other symbols are as defined in claim 1; and non-toxic salts thereof.

Piperidine derivatives according to claim 1, wherein the general formula I corresponds to the general formula I wherein all the general symbols have the meaning given in claim 1; and non-toxic salts thereof.

Piperidine derivatives according to claim 2, wherein R ⁶ 'is hydroxy.

The piperidine derivatives of claim 2, wherein R ⁶ is C 1-8 alkoxy or C 1-8 alkoxy substituted by phenyl.

Piperidine derivatives according to claim 4 which are (1) 2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid, (3) 2- (4- (3-ethoxy-4-methoxyphenyl-4-cyanopiperidin-1-yl) acetic acid, 4-dimethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid; ) 2- (4- (3-cyclopropylmethoxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid, (S) 2- (4- (3-isopropyloxy-4-methoxyphenyl) -4-cyanopiperidine- 1-yl) acetic acid, (6) 2- (4- (3-cyclobutyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid, (7) 2- (4- (3-cyclopentyloxy-4) (8) 4- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) butanoic acid, (9) -methoxyphenyl) -4-cyanopiperidin-1-yl) -propanoic acid; 2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) butyric acid, (10) 2- (4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -4-cyanopiperidine- 1-yl) acetic acid, (11) 2- (4- (3-cyclopentyloxy-4-ethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid, (12) 2- (4- (3-cyclopentyloxy-4-ethoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid, (13) 2- (4- (3-cyclopentyloxy-4-isopropyloxyphenyl) -4-cyanopiperidin-1-yl) acetic acid (14) 2- (4- (3-isopropyloxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid, (15) 2- (4- (3-cyclohexyloxy-4-difluoromethoxyphenyl) -4 -cyanopiperidin-1-yl) acetic acid, (16) 3- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid, (17) (2R) -2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid, (18) (2S) -2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidine) -1-yl) propanoic acid, (19) 2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) -2-methylpropanoic acid, (20) 1- (4- ( 3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid, (21) 1- (4- (3-ethoxy-4-methoxyphenyl-4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid (22) 1- (4- (3-Cyclopropylmethoxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclo propanecarboxylic acid, (23) 1- (4- (3-cyclobutyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid, (24) 2- (4- (3- (indan-2- yloxy) -4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid; (25) 2- (4- (3-cyclobutyloxy- 4-Difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid, (26) 2- (4- (3- (indan-2-yloxy) -4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) - acetic acid, (27) 2- (4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid, (28) 2- (4- (3-cyclobutylmethoxy-4-difluoromethoxyphenyl) - 4-cyanopiperidin-1-yl) acetic acid, (29) 2- (4- (3-ethoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid, (30) 2- (4- (3) -butoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid, (31) 2- (4- (3-propoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid, (32) ) 2- (4- (3- (2-methylpropoxy) -4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid and (33) 2- (4- (3-cy clopentyloxy-4-methoxyphenyl) piperidin-1-yl) acetic acid.

The piperidine derivatives of claim 5 which are (1) 2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester, (2) 2- (4- (ethyl) ethyl ester) 3,4-dimethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid, (3) 2- (4- (3-ethoxy-4-methoxyphenyl-4-cyanopiperidin-1-yl) acetic acid ethyl ester, (4) 2- (4- (3-cyclopropylmethoxy-4-methoxyphenyl) -4-cyano-piperidin-1-yl) acetic acid ethyl ester, (5) 2- (4- (3-isopropyloxy-4-methoxyphenyl) -4-cyanopiperidine ethyl ester) (6) ethyl 2- (4- (3-cyclobutyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid, (7) 2- (4- (3-) ethyl ester cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid, (8) 4- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) butanoic acid ethyl ester, (9) ) 2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) butanoic acid ethyl ester, (10) 2- (4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -4-cyano ethyl ester) -piperidin-1-yl) acetic acid, (11) 2- (4- (3-cyclopentyloxy-4-ethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester; (12) 2- (4- (3-cyclopentyloxy-4) ethyl ester) (13) 2- (4- (3-cyclopentyloxy-4-isopropyloxyphenyl) -4-cyano-piperidin-1-yl) -acetic acid ethyl ester, (14) ethyl ester 2- (4- (3-isopropyloxy-4-difluoromethoxyphenyl) -4-cyano-piperidin-1-yl) acetic acid; (15) 2- (4- (3-cyclohexyloxy-4-difluoromethoxyphenyl) -4-cyano-) ethyl ester; piperidin-1-yl) acetic acid, (16) 3- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanoic acid methyl ester, (17) (2R) -2- (4) methyl ester - (3-cyclopentyloxy-4-methoxyphenyl) -4-cyano-piperidin-1-yl) propanoic acid, (18) (2S) -2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyano-) methyl ester. piperidin-1yl) propanoic acid, (19) 2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) -2-methylpropanoic acid benzyl ester, (20) 1- (4- (benzyl) benzyl ester) 3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperide (1-yl) cyclopropanecarboxylic acid, (21) 1- (4- (3-ethoxy-4-methoxyphenyl-4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid benzyl ester), (22) 1- (4- (3-) benzyl ester methoxymethoxy-4-methoxyphenyl) -4-cyano-piperidin-1-yl) cyclopropanecarboxylic acid, (23) 1- (4- (3-hydroxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclopropanecarboxylic acid benzyl ester, (24) ) 1- (4- (3-cyclopropylmethoxy-4-methoxyphenyl) -4-cyano-piperidin-1-yl) cyclopropanecarboxylic acid benzyl ester, (25) 1- (4- (3-cyclobutyloxy-4-methoxyphenyl) -4-) benzyl ester cyanopiperidin-1-yl) cyclopropanecarboxylic acid, (26) 2- (4- (3-benzyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid ethyl ester, (27) 2- (4- (methyl) methyl ester) 3-benzyloxy-4-difluoromethoxyphenyl) -4-cyano-piperidin-1-yl) acetic acid, (28) 2- (4- (3-hydroxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) -acetic acid ethyl ester (29) 2- (4- (3-hydroxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid methyl ester, (30) 2- (4- (3- ( indan-2-yloxy) -4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid; (31) 9- (31) methyl ester 2- ( 4- (3-cyclobutyloxy-4-difluoromethoxyphenyl) -4-cyano-piperidin-1-yl) acetic acid, (32) 2- (4- (3- (indan-2-yloxy) -4-difluoromethoxyphenyl) -4-difluoromethoxyphenyl) -4-methyl ester (33) 2- (4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid methyl ester, (34) 2- (4- (methyl) -piperidin-1-yl) acetic acid methyl ester (3-cyclobutylmethoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid, (35) 2- (4- (3-ethoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid methyl ester , (36) 2- (4- (3-butoxy-4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid methyl ester, (37) 2- (4- (3-propoxy-4-difluoromethoxyphenyl) -) methyl ester - 4-cyanopiperidin-1-yl) acetic acid, (38) 2- (4- (3- (2-methylpropoxy) -4-difluoromethoxyphenyl) -4-cyanopiperidin-1-yl) acetic acid methyl ester, and (39) ethyl 2- (4- (3-Cyclopentyloxy-4-methoxyphenyl) pip eridin-1-yl) acetic acid.

Piperidine derivatives according to claim 3 which are (1) N-hydroxy-2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetamide, (2) N-hydroxy-2 - (4- (3,4-dimethoxyphenyl) -4-cyanopiperidin-1-yl) acetamide, (3) N-hydroxy-2- (4- (3-ethoxy-4-methoxyphenyl-4-cyanopiperidin-1-yl)) (4) N-hydroxy-2- (4- (3-cyclopropylmethoxy-4-methoxyphenyl) -4-cyano-piperidin-1-yl) acetamide; (5) N-hydroxy-2- (4- (3) (6) N-hydroxy-2- (4- (3-cyclobutyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) acetamide, (7) N-hydroxy-2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanamide; (8) N-hydroxy-4- (4- (3-cyclopentyloxy-4)); (9) N-hydroxy-2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) butanamide, (10) N-methoxyphenyl) -4-cyanopiperidin-1-yl) butanamide; -hydroxy-2- (4- (3-cyclopentyloxy-4-difluoromethoxyphenyl) -4-cyano-piperidin-1-yl) acetamide, (11) N-hydroxy-2- (4- (3-cyclopentyloxy-4-ethoxyphenyl)) (12) N-Hydroxy-4-cyanopiperidin-1-yl) acetamide; xy-2- (4- (3-cyclopentyloxy-4-ethoxyphenyl) -4-cyanopiperidin-1-yl) propanamide, (13) N-hydroxy-2- (4- (3-cyclopentyloxy-4-isopropyloxyphenyl) -4 (14) N-hydroxy-3- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) propanamide, (15) (2R) -N- (3-cyano-piperidin-1-yl) acetamide; hydroxy-2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyano-piperidin-1-yl) propanamide, (16) (2S) -N-hydroxy-2- (4- (3-cyclopentyloxy-4-) (17) N-hydroxy-2- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) -2-methylpropanamide (18-methoxyphenyl) -4-cyano-piperidin-1-yl) propanamide; N-hydroxy-1- (4- (3-cyclopentyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclopropanecarboxamide, (19) N-hydroxy-1- (4- (3-ethoxy-4-methoxyphenyl) (20) N-hydroxy-1- (4- (3-cyclopropylmethoxy-4-methoxyphenyl) -4-cyano-piperidin-1-yl) cyclopropanecarboxamide and (21) N- (4-cyanopiperidin-1-yl) cyclopropanecarboxamide; hydroxy-1- (4- (3-cyclobutyloxy-4-methoxyphenyl) -4-cyanopiperidin-1-yl) cyclopropanecarboxamide.

A PDE4 inhibitor which comprises as active ingredient a piperidine derivative of the formula I according to claim 1 or a non-toxic salt thereof.

An agent for preventing and / or treating inflammatory diseases, for example asthma, obstructive pulmonary disease, sepsis, sarcoidosis, nephritis, hepatitis and enteritis; diabetic diseases; allergic diseases such as allergic rhinitis, allergic conjunctivitis, seasonal conjunctivitis and atopic dermatitis; autoimmune diseases such as ulcerative colitis, Crohn's disease, rheumatism, psoriasis, multiple sclerosis, and collagen diseases; osteoporosis; bone fractures; obesity; depression; Parkinson's disease; dementia; ischemic reperfusion injury; leukemia and AIDS, characterized in that the active ingredient is a piperidine derivative of the formula I according to claim 1 or a non-toxic salt thereof.